Molecular machines in biology

Molecular machines in biology

https://reasonandscience.catsboard.com/t1289-molecular-machines-in-biology

Definitions

A machine is a piece of equipment with several moving parts that uses power to do a particular type of work
https://dictionary.cambridge.org/dictionary/english/machine

A machine is an assembly of interconnected components arranged to transmit or modify force in order to perform useful work. Proteins are made of several interconnected subunits, and perform a specific function, using ATP as an energy source.

K. Eric Drexler: Engines of Creation 2.0 2006
“Any system, usually of rigid bodies, formed and connected to alter, transmit, and direct applied forces  in a predetermined manner to accomplish a specific  objective, such as the performance of useful work.”  Molecular machines fit this definition quite well.

1. Machines are always designed.
2. Proteins are machines.
3. Therefore, proteins were designed.

Michael Denton (1986): Evolution, A Theory in Crisis, , p234 
Protein molecules are the ultimate stuff of life. If we think of the cell as being analogous to a factory, then the proteins can be thought of as analogous to the machines on the factory floor which carry out individually or in groups all the essential activities on which the life of the cell depends. Each protein is a sort of micro-miniaturized machine, so small that it must be magnified a million times before it is visible to the human eye. The structure and functioning of these fascinating workhorses of the cell was a complete mystery until the 1950s. 

A. G. CAIRNS-SMITH Seven clues to the origin of life, page 66
Once you think you will need machines, then you will think that you need a lot. If. for example, the organism has to have some kind of printing machinery in it, so that it can replicate its genetic information, then it will need manufacturing machinery also to make this printing machinery. And then this manufacturing machinery, some sort of robot, must also be able to make other machines exactly like itself. The circle closes eventually, but not until after a long journey - too long to be a practicable piece of engineering even for us, and much too long for Nature before its engineer, natural selection, had come on the scene.

Membranes to Molecular Machines: Active Matter and the Remaking of Life Mathias Grote
Today's science tells us that our bodies are filled with molecular machinery that orchestrates all sorts of life processes. When we think, microscopic "channels" open and close in our brain cell membranes; when we run, tiny "motors" spin in our muscle cell membranes; and when we see, light operates "molecular switches" in our eyes and nerves. A molecular-mechanical vision of life has become commonplace in both the halls of philosophy and the offices of drug companies, where researchers are developing “proton pump inhibitors” or medicines similar to Prozac.


Physics and chemistry cannot reveal the practical principles of design or co-ordination which are the structure of the machine.
http://echo.iat.sfu.ca/library/polanyi_70_transcendence.pdf

Proteins perform vital functions of life, they digest food and fight infections and cancer. They are in fact nano-machines, each one of them designed to perform a specific task.
https://www.nanowerk.com/nanotechnology-news/newsid=46811.php

Molecular machines are the basis of life. The cell’s nanometer-scale machines are mostly protein molecules, although a few are made from RNA, and they are capable of surprisingly complex manipulations. They perform almost all the important active tasks in the cell: metabolism, reproduction, response to changes in the environment, and so forth. They are incredibly sophisticated, and they, not their manmade counterparts, represent the pinnacle of nanotechnology. 
https://physicstoday.scitation.org/doi/10.1063/1.2216960

A machine is a device with interacting parts that operate in a coordinated fashion to produce a predetermined outcome. Machines can be described in terms of a list of parts and a blueprint indicating how those parts fit together, meaning that someone who has never seen a particular kind of machine should in principle be able to assemble any number of copies each virtually identical in appearance and performance—provided they can consult the machine’s design specifications. Second, as machines are designed to perform highly specific functions, their operation is tightly constrained, which is why it is possible to predict and control their behavior. Third, machines are highly efficient in what they do because they always follow the exact same sequence of steps in every cycle of their operation. And fourth, the operation of machines is not continuous; their functioning can be interrupted and their parts examined without thereby jeopardizing their structural integrity.
https://www.sciencedirect.com/science/article/abs/pii/S0022519319302292?via%3Dihub

The problem with engineering metaphors in molecular biology
https://philpapers.org/archive/NICOBT-2.pdf
“ ‘[m]achine’ is useful as a concept because the molecular assemblies [. . .] share important properties with their macroscopic counterparts, such as processivity, localized interactions, and the fact that they perform work toward making a defined product.”

“a molecular machine we are able to switch between two [or more] molecular states (shapes) in a controlled manner as part of a repetitious mechanical cycle.”

Alberts,  has been one of the most influential advocates of the molecular machine metaphor in molecular biology during the last two decades. He gives the following explanation: 

Why do we call the large protein assemblies that underlie cell function protein machines? Precisely because, like the machines invented by humans to deal efficiently with the macroscopic world, these protein assemblies contain highly coordinated moving parts. Within each protein assembly, intermolecular collisions are not only restricted to a small set of possibilities but the reaction C depends on reaction B, which in turn depends on reaction A – just as it would in a machine of our common experience.

Cells contain fully automated manufacturing production lines, transport carriers oriented by sophisticated GPS systems, incredibly efficient turbines, transistors, billions of interlinked computers like the WWW, communication systems like 5G, complex machines and robots, and factories interlinked into factory parks, literally cities. Is it reasonable to believe that they can emerge by random chance?

Molecular Machines Putting the Pieces Together 2001 Jan 8
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2193665/
Most functions in the cell are not carried out by single protein enzymes, colliding randomly within the cellular jungle, but by macromolecular complexes containing multiple subunits with specific functions.  Many of these complexes are described as “molecular machines.” Indeed, this designation captures many of the aspects characterizing these biological complexes: modularity, complexity, cyclic function, and, in most cases, the consumption of energy.

Biological machines: from mills to molecules 4
More than three centuries ago, the birth of modern life sciences was marked by the idea that body function is based on organic  machines whose performance can be explained by similar laws to those operating in man-made machines. In the seventeenth century, this concept was used not only to explain functions that obviously reflected those of mechanical devices (such as skeletal and articular motion or the action of muscles), but also for other operations — digestion, sensation, fermentation and production of blood. To account for these more delicate operations of animal economy, body machines were thought to involve tiny components that could escape detection by the naked eye. This view derived, in part, from a recurrence of the physicists’ view that the Universe is composed of atoms. In Greek classical science this view was advocated by Democritus, and in the seventeenth century by the French philosopher and scientist Pierre Gassendi. As Marcello Malpighi (FIG. 1), one of the greatest seventeenth-century life scientists put it :

“Nature, in order to carry out the marvellous operations in animals and plants, has been pleased to construct their organized bodies with a very large number of machines, which are of necessity made up of extremely minute parts so shaped and situated, such as to form a marvellous organ, the composition of which are usually invisible to the naked eye, without the aid of the microscope.

To an extent, these extraordinary biological machines realize the dream of the seventeenth-century scientists — a dream that led Malpighi to suppose, more than three centuries ago, that

“machines will be eventually found not only unknown to us but also unimaginable by our mind”
Malpighi, M. The Viscerum Structura (Montii, Bologna,1666)

It became increasingly clear that the function of enzymes depends not only on their elementary chemical composition, but also on the configuration of their components. For example, effective interactions between enzymes, substrates and cofactors depend on the spatial arrangement of the interacting elements. This insight led to interest in the structure of complex molecules. It was also evident that the function of enzymes and other biological molecules could be regulated through specific control mechanisms.

An important advance has been the recognition that complex receptor assemblies are linked to second messenger systems through specialized proteins34,35 and that there is a flux of biological information. This information is carried by specific messengers, which act on systems that recognize them and develop specific responses. Through this complex flux of information, different mechanisms can be organized in more complex systems, resulting in highly integrated and efficient processes 

 ‘Structure’ is fundamental to the operation of modern molecular devices: for example, take the threedimensional arrangement of individual molecules; the spatial arrangement of proteins in sequential operations; and the arrangement of different proteins in a given process with respect to the membranes surrounding subcellular organelles or the cell as a whole. Given the importance of structure, modern biological pathways fully deserve the names “molecular and supramolecular machines


The concept of molecular machines in biology has transformed the medical field in a profound way. Many essential processes that occur in the cell, including transcription, translation, protein folding, and protein degradation, are all carried out by molecular machines. 1

Molecular machines cannot perform their functions until many parts are present and coordinated, they cannot be built by the "numerous, successive, slight modifications" required by Darwinian evolution. As Behe notes, "The complexity of life's foundation has paralyzed science's attempt to account for it; molecular machines raise an as-yet impenetrable barrier to Darwinism's universal reach."  3

Proteins are the machinery of living tissue that builds the structures and carries out the chemical reactions necessary for life. 2   For example, the first of many steps necessary for the conversion of sugar to biologically-usable forms of energy is carried out by a protein called hexokinase. Skin is made in large measure of a protein called collagen. When light impinges on your retina it interacts first with a protein called rhodopsin. As can be seen even by this limited number of examples proteins carry out amazingly diverse functions. However, in general a given protein can perform only one or a few functions: rhodopsin cannot form skin and collagen cannot interact usefully with light. Therefore a typical cell contains thousands and thousands of different types of proteins to perform the many tasks necessary for life, much like a carpenter's workshop might contain many different kinds of tools for various carpentry work.

What do these versatile tools look like? The basic structure of proteins is quite simple: they are formed by hooking together in a chain discrete subunits called amino acids. Although the protein chain can consist of anywhere from about 50 to about 1,000 amino acid links, each position can only contain one of twenty different amino acids. In this way they are much like words: words can come in various lengths but they are made up from a discrete set of 26 letters. Now, a protein in a cell does not float around like a floppy chain; rather, it folds up into a very precise structure which can be quite different for different types of proteins. When all is said and done two different amino sequences--two different proteins--can be folded to structures as specific as and different from each other as a three-eighths inch wrench and a jigsaw. And like the household tools, if the shape of the proteins is significantly warped then they fail to do their jobs.

1. http://www.cambridge.org/us/academic/subjects/life-sciences/molecular-biology-biochemistry-and-structural-biology/molecular-machines-biology-workshop-cell
2. http://www.arn.org/docs/behe/mb_mm92496.htm
3. http://www.salvomag.com/new/articles/salvo20/molecular-machines-evidence-for-design.php#sthash.srAVxYUz.dpuf
4. https://sci-hub.tw/http://www.nature.com/nrm/journal/v1/n2/full/nrm1100_149a.html?foxtrotcallback=true

Some links:
http://en.wikipedia.org/wiki/Molecular_machine


https://www.youtube.com/watch?v=zm-3kovWpNQ
06:38
now this next picture is showing you a more realistic bigger protein molecule most protein molecules are bigger than the one I just showed you they often look something like this and now I want to switch from talking about the folding problem per se to talking about mechanisms and functions and the case I want to make for you is that proteins are machines YOU HAVE 20,000 DIFFERENT TYPES OF MACHINES in your body and then other kinds of living organisms have other kinds of protein machines there's tens of thousands to hundreds of thousands of different machines and the first case I want to make for you is that these are real machines that's not a metaphor they use energy they spin around they pump they act to cause force and motion

Molecular Machines in the Cell

Long before the advent of modern technology, students of biology compared the workings of life to machines.1 In recent decades, this comparison has become stronger than ever. As a paper in Nature Reviews Molecular Cell Biology states, “Today biology is revealing the importance of ‘molecular machines’ and of other highly organized molecular structures that carry out the complex physico-chemical processes on which life is based.”2 Likewise, a paper in Nature Methods observed that “[m]ost cellular functions are executed by protein complexes, acting like molecular machines.”

A molecular machine, according to an article in the journal Accounts of Chemical Research, is “an assemblage of parts that transmit forces, motion, or energy from one to another in a predetermined manner.”4 A 2004 article in Annual Review of Biomedical Engineering asserted that “these machines are generally more efficient than their macroscale counterparts,” further noting that “[c]ountless such machines exist in nature.”5 Indeed, a single research project in 2006 reported the discovery of over 250 new molecular machines in yeast alone!6

Molecular machines have posed a stark challenge to those who seek to understand them in Darwinian terms as the products of an undirected process. In his 1996 book Darwin’s Black Box: The Biochemical Challenge to Evolution, biochemist Michael Behe explained the surprising discovery that life is based upon machines:

Shortly after 1950 science advanced to the point where it could determine the shapes and properties of a few of the molecules that make up living organisms. Slowly, painstakingly, the structures of more and more biological molecules were elucidated, and the way they work inferred from countless experiments. The cumulative results show with piercing clarity that life is based on machines--machines made of molecules! Molecular machines haul cargo from one place in the cell to another along "highways" made of other molecules, while still others act as cables, ropes, and pulleys to hold the cell in shape. Machines turn cellular switches on and off, sometimes killing the cell or causing it to grow. Solar-powered machines capture the energy of photons and store it in chemicals. Electrical machines allow current to flow through nerves. Manufacturing machines build other molecular machines, as well as themselves. Cells swim using machines, copy themselves with machinery, ingest food with machinery. In short, highly sophisticated molecular machines control every cellular process. Thus, the details of life are finely calibrated and the machinery of life enormously complex.7

Behe then posed the question, “Can all of life be fit into Darwin’s theory of evolution?,” and answered: "The complexity of life's foundation has paralyzed science's attempt to account for it; molecular machines raise an as-yet impenetrable barrier to Darwinism's universal reach."8

Even those who disagree with Behe’s answer to that question have marveled at the complexity of molecular machines. In 1998, former president of the U.S. National Academy of Sciences Bruce Alberts wrote the introductory article to an issue of Cell, one of the world’s top biology journals, celebrating molecular machines. Alberts praised the “speed,” “elegance,” “sophistication,” and “highly organized activity” of “remarkable” and “marvelous” structures inside the cell. He went on to explain what inspired such words:

The entire cell can be viewed as a factory that contains an elaborate network of interlocking assembly lines, each of which is composed of a set of large protein machines. . . . Why do we call the large protein assemblies that underlie cell function protein machines? Precisely because, like machines invented by humans to deal efficiently with the macroscopic world, these protein assemblies contain highly coordinated moving parts.9

Likewise, in 2000 Marco Piccolini wrote in Nature Reviews Molecular Cell Biology that “extraordinary biological machines realize the dream of the seventeenth- century scientists … that ‘machines will be eventually found not only unknown to us but also unimaginable by our mind.’” He notes that modern biological machines “surpass the expectations of the early life scientists.”10

A few years later, a review article in the journal Biological Chemistry demonstrated the difficulty evolutionary scientists have faced when trying to understand molecular machines. Essentially, they must deny their scientific intuitions when trying to grapple with the complexity of the fact that biological structures appear engineered to the schematics of blueprints:

Molecular machines, although it may often seem so, are not made with a blueprint at hand. Yet, biochemists and molecular biologists (and many scientists of other disciplines) are used to thinking as an engineer, more precisely a reverse engineer. But there are no blueprints … ‘Nothing in biology makes sense except in the light of evolution’: we know that Dobzhansky (1973) must be right. But our mind, despite being a product of tinkering itself strangely wants us to think like engineers.11

But do molecular machines make sense in the light of undirected Darwinian evolution? Does it make sense to deny the fact that machines show all signs that they were designed? Michael Behe argues that in fact molecular machines meet the very test that Darwin posed to falsify his theory, and indicate intelligent design.

Darwin knew his theory of gradual evolution by natural selection carried a heavy burden:

If it could be demonstrated that any complex organ existed which could not possibly have been formed by numerous, successive, slight modifications, my theory would absolutely break down.

… What type of biological system could not be formed by “numerous successive slight modifications”? Well, for starters, a system that is irreducibly complex. By irreducibly complex I mean a single system which is composed of several interacting parts that contribute to the basic function, and where the removal of any one of the parts causes the system to effectively cease functioning.12

Molecular machines are highly complex and in many cases we are just beginning to understand their inner workings. As a result, while we know that many complex molecular machines exist, to date only a few have been studied sufficiently by biologists so that they have directly tested for irreducible complexity through genetic knockout experiments or mutational sensitivity tests. What follows is a non-exhaustive list briefly describing 40 molecular machines identified in the scientific literature. The first section will cover molecular machines that scientists have argued show irreducible complexity. The second section will discuss molecular machines that may be irreducibly complex, but have not been studied in enough detail yet by biochemists to make a conclusive argument.

Steve Benner, at 8:30
Here this is a structure of something that you have in your bodies it's called the ribosome it is actually the molecular machine that makes proteins
https://www.youtube.com/watch?v=jhk_QCTrysU


Selected list of molecular machines:

I. Molecular Machines that Scientists Have Argued Show Irreducible Complexity

1. Bacterial Flagellum: The flagellum is a rotary motor in bacteria that drives a propeller to spin, much like an outboard motor, powered by ion flow to drive rotary motion. Capable of spinning up to 100,000 rpm,13 one paper in Trends in Microbiology called the flagellum “an exquisitely engineered chemi-osmotic nanomachine; nature’s most powerful rotary motor, harnessing a transmembrane ion-motive force to drive a filamentous propeller.”14 Due to its motor-like structure and internal parts, one molecular biologist wrote in the journal Cell, “[m]ore so than other motors, the flagellum resembles a machine designed by a human.”15 Genetic knockout experiments have shown that the E. coli flagellum is irreducibly complex with respect to its approximately 35 genes.16 Despite the fact that this is one of the best studied molecular machines, a 2006 review article in Nature Reviews Microbiology admitted that “the flagellar research community has scarcely begun to consider how these systems have evolved.”17

2. Eukaryotic Cilium: The cilium is a hair-like, or whip-like structure that is built upon a system of microtubules, typically with nine outer microtubule pairs and two inner microtubules. The microtubules are connected with nexin arms and a paddling-like motion is instigated with dynein motors.18 These machines perform many functions in Eukaryotes, such as allowing sperm to swim or removing foreign particles from the throat. Michael Behe observes that the “paddling” function of the cilium will fail if it is missing any microtubules, connecting arms, or lacks sufficient dynein motors, making it irreducibly complex.19

3. Aminoacyl-tRNA Synthetases (aaRS): aaRS enzymes are responsible for charging tRNAs with the proper amino acid so they can accurately participate in the process of translation. In this function, aaRSs are an “aminoacylation machine.”20 Most cells require twenty different aaRS enzymes, one for each amino acid, without which the transcription/translation machinery could not function properly.21 As one article in Cell Biology International stated: “The nucleotide sequence is also meaningless without a conceptual translative scheme and physical ‘hardware’ capabilities. Ribosomes, tRNAs, aminoacyl tRNA synthetases, and amino acids are all hardware components of the Shannon message ‘receiver’. But the instructions for this machinery is itself coded in DNA and executed by protein ‘workers’ produced by that machinery. Without the machinery and protein workers, the message cannot be received and understood. And without genetic instruction, the machinery cannot be assembled.”22 Arguably, these components form an irreducibly complex system.23

4. Blood clotting cascade: The blood coagulation system “is a typical example of a molecular machine, where the assembly of substrates, enzymes, protein cofactors and calcium ions on a phospholipid surface markedly accelerates the rate of coagulation.”24 According to a paper in BioEssays, “the molecules interact with cell surface (molecules) and other proteins to assemble reaction complexes that can act as a molecular machine.”25 Michael Behe argues, based upon experimental data, that the blood clotting cascade has an irreducible core with respect to its components after its initiation pathways converge.26

5. Ribosome: The ribosome is an “RNA machine”27 that “involves more than 300 proteins and RNAs”28 to form a complex where messenger RNA is translated into protein, thereby playing a crucial role in protein synthesis in the cell. Craig Venter, a leader in genomics and the Human Genome Project, has called the ribosome “an incredibly beautiful complex entity” which requires a “minimum for the ribosome about 53 proteins and 3 polynucleotides,” leading some evolutionist biologists to fear that it may be irreducibly complex.29

6. Antibodies and the Adaptive Immune System: Antibodies are “the ‘fingers’ of the blind immune system—they allow it to distinguish a foreign invader from the body itself.”30 But the processes that generate antibodies require a suite of molecular machines.31 Lymphocyte cells in the blood produce antibodies by mixing and match portions of special genes to produce over 100,000,000 varieties of antibodies.32 This “adaptive immune system” allows the body to tag and destroy most invaders. Michael Behe argues that this system is irreducibly complex because many components must be present for it to function: “A large repertoire of antibodies won’t do much good if there is no system to kill invaders. A system to kill invaders won’t do much good if there’s no way to identify them. At each step we are stopped not only by local system problems, but also by requirements of the integrated system.”33

II. Additional Molecular Machines

7. Spliceosome: The spliceosome removes introns from RNA transcripts prior to translation. According to a paper in Cell, “In order to provide both accuracy to the recognition of reactive splice sites in the pre-mRNA and flexibility to the choice of splice sites during alternative splicing, the spliceosome exhibits exceptional compositional and structural dynamics that are exploited during substrate-dependent complex assembly, catalytic activation, and active site remodeling.”34 A 2009 paper in PNAS observed that “[t]he spliceosome is a massive assembly of 5 RNAs and many proteins”35—another paper suggests “300 distinct proteins and five RNAs, making it among the most complex macromolecular machines known.”36

8. F0F1 ATP Synthase: According to cell biologist and molecular machine modeler David Goodsell, “ATP synthase is one of the wonders of the molecular world.”37 This protein-based molecular machine is actually composed of two distinct rotary motors which joined by a stator: As the F0 motor is powered by protons, it turns the F1 motor. This kinetic energy is used like a generator to synthesize adenosine triphosphate (ATP), the primary energy carrying molecule of cells.38

9. Bacteriorhdopsin: Bacteriorhodopsin “is a compact molecular machine” uses that sunlight energy to pump protons across a membrane.39 Embedded in the cell membrane, it consists of seven helical structures that span the membrane. It also contains retinal, a molecule which changes shape after absorbing light. Photons captured by retinal are forced through the seven helices to the outside of the membrane.40 When protons flow back through the membrane, ATP is formed.

10. Myosin: Myosin is a molecular motor that moves along a “track”—in this case actin filaments—to form the basis of muscle movement or to transport cargoes within the cell.41 Muscles use molecular machines like myosin to “convert chemical energy into mechanical energy during muscle contraction.”42 In fact, muscle movement requires the “combined action of trillions of myosin motors.”43

11. Kinesin Motor: Much like myosin, kinesin is a protein machine that binds to and carries cargoes by “crawls hand-over-hand along a microtubule” in the cell.44 Kinesins are powerful enough to drag large cellular organelles through the cell as well as vesicles or aid in assembly of bipolar spindles, or depolymerization of microtubules.45

12. Tim/Tom Systems: Tim or Tom systems are selective protein pump machines that import proteins across the inner (Tim) and outer (Tom) membranes of mitochondria into the interior matrix of the mitochondria.46

13. Calcium Pump: The calcium pump is an “amazing machine with several moving parts“ that transfers calcium ions across the cell membrane. It is a machine that uses a 4-step cycle during the pump process.47

14. Cytochrome C Oxidase: Cytochrome C Oxidase qualifies as a molecular machine “since part of the redox free energy is transduced into a proton electrochemical gradient.”48 The enzyme’s function is to carefully control the final steps of food oxidation by combining electrons with oxygen and hydrogen to form water, thereby releasing energy. It uses copper and iron atoms to aid in this process.49

15. Proteosome: The proteosome is a large molecular machine whose parts must be must be carefully assembled in a particular order. For example, the 26S proteosome has 33 distinct subunits which enable it to perform its function to degrade and destroy proteins that have been misfolded in the cell or otherwise tagged for destruction.50 One paper suggested that a particular eukaryotic proteasome “is the core complex of an energy-dependent protein degradation machinery that equals the protein synthesis machinery in its complexity.”51

16. Cohesin: Cohesin is molecular machine “multisubunit protein complex"52 and “a macromolecular complex that links sister chromatids together at the metaphase plate during mitosis.”53

17. Condensin: Condensin is a molecular machine that helps to condense and package chromosomes for cell replication. It is a five subunit complex, and is “the key molecular machine of chromosome condensation.”54

18. ClpX: ClpX is a molecular machine that uses ATP to both unfold proteins and then transport unfolded proteins into another complex in the cell. It moves these proteins into the ClpP complex.55

19. Immunological Synapse: The immunological synapse is a molecular machine that serves as an interface to activate of T cells. Once an immunological synapse is completely formed, T Cells are activated and proliferate, sparking key part of the immune response.56

20. Glideosome: The glideosome is a “macromolecular complex” and an “elaborate machine”57 whose function is to allow protozoa to rely on gliding motility over various substrates.

21. Kex2: Kex2 is a molecular machine that facilitates cell fusion during the mating of yeast; it likely works by degrading cell walls.58

22. Hsp70: Hsp70 is one of many molecular machines that serve as chaperones that not only assist other proteins in reaching a proper functional conformation (i.e. proper folding) but also helping them to be transported to the proper location in the cell.59

23. Hsp60: Hsp60 is another chaperone machine – it is tailored to provide “an enclosed environment for folding proteins which totally protects them as they fold.”60 It is composed of multiple proteins which form a barrel shaped structure with a cap.61 Once an unfolded protein is inside, it can fold properly.

24. Protein Kinase C: Protein Kinase C is a molecular machine that is activated by certain calcium and diacylglycerol signals in the cell. It thus acts as an interpreter of electrical signals, as one paper in Cell wrote: “This decoding mechanism may explain how cPKC isoforms can selectively control different cellular processes by relying on selective patterns of calcium and diacylglycerol signals.”62

25. SecYEG PreProtein Translocation Channel: The SecYE complex is vital to the operation of “translocation machinery” which works to move molecules across membranes in the cell.63

26. Hemoglobin: Molecular machine modeller David Goodsell observes that “Hemoglobin is a remarkable molecular machine that uses motion and small structural changes to regulate its action.”64 Hemoglobin uses iron within its protein structure to carry oxygen from the lungs to the rest of the body through the blood.

27. T4 DNA Packaging Motor: The T4 DNA is one of various packaging motors that are “powerful molecular motors” which emplace viral genomes into capsules called procapsids.65 Once viral genome packaging is complete, “the DNA packaging motor is released and the separately assembled tail is attached to produce the mature infectious viral particle.”66

28. Smc5/Smc6: Smc5/Smc6 is a complex machine that is involved with the structural maintenance of chromosomes with regards to cohesions and condensins,67 and works to remove cohesin from damaged chromosomes prior to chromosomal separation,68 and may also work to repair and untangle DNA.69

29. Cytplasmic Dynein: Cytplasmic dynein is a machine involved with cargo transport and movement cell that functions like a motor with a “power stroke.”70 In particular, it transports nuclei in fungi and neurons in mammalian brains.71

30. Mitotic Spindle Machine: The mitotic spindle is a highly dynamic self-assembling complex molecular machine composed of tubulin, motors, and other molecules which assembles around the chromosomes and segregates them into daughter cells during mitosis.72

31. DNA Polymerase: The DNA polymerase is a multiprotein machine that creates a complementary strand of DNA from a template strand.73 The DNA polymerase is not only the “central component of the DNA replication machinery,”74 but it “plays the central role in the processes of life,”75 since it is responsible for the copying of DNA from generating to generation. During the polymerization process, it remains tethered to the DNA using a protein-based sliding clamp.76 It is extremely accurate, making less than one mistake per billion bases, aided by its ability to proofread and fix mistakes.77

32. RNA Polymerase: Like its DNA polymerase counterpart, the function of the RNA polymerase is to create a messenger RNA strand from a DNA template strand. Called "a huge factory with many moving parts,"78 it is a “directional machine and, indeed, as a molecular motor” where it functions “as a dynamic, fluctuating, molecular motor capable of producing force and torque.”79

33. Kinetochore: The kinetochore is a “proteinaceous structure that assembles on centromeric chromatin and connects the centromere to spindle microtubules.”80 Called a “macromolecular protein machine,”81 it is composed of over 80 protein components;82 it aids in separating chromosomes during cell division.

34. MRX Complex: The MRX complex forms telomere length counting machinery that measures the integrity of telomeres, the structures that protect the ends of eukaryotic chromosomes. Properly measuring telomere length is vital to ensure proper cell lifetime and genome stability.83 Yeast use the MRX complex via a “’protein-counting’ mechanism whereby higher numbers of proteins bound by a longer telomere repeat tract ultimately inhibit telomerase activity at that particular telomere.”84

35. Apoptosome / Caspase: While many molecular machines keep a cell alive, there are even machines that are programmed to cause cell death, or apoptosis. Cell death must be carefully timed so that cells die when they need to be replaced. According to David Goodsell, “Caspases are the executioners of apoptosis,” and they work by destroying specific proteins in the right order so as to “disassemble the cell in an orderly manner.”85 Caspases can be part of a “death machine” called the apoptosome,86 a molecular machine which receives signals indicating cellular stress and then initiates cell death, including activity of caspases.

36. Type III Secretory System: This machine, often called the T3SS, is a toxin injection machine used by predatory bacteria to deliver deadly toxins into other cells.87 It is composed of subunits that are machines, such as the injectisome nanomachine.88

37. Type II Secretion Apparatus: The T2SS is a complex nanomachine that translocates proteins across the outer membrane of a bacterium.89

38. Helicase/Topoisomerase Machine: The helicase and topoisomerase machines work together to properly unwrap or unzip DNA prior to transcription of DNA into mRNA or DNA replication.90 Topoisomerase performs this function by cutting one DNA strand and then holding on to the other while the cut strand unwinds.91

39. RNA degradasome: The RNA degradasome “multiprotein complex involved in the degradation of mRNA”92 or trimming RNAs into their active forms93 in E. coli bacteria. Its large size “would readily qualify [it] as a supramolecular machine dedicated to RNA processing and turnover.”94

40. Photosynthetic system: The processes that plants use to convert light into chemical energy a type of molecular machines.95 For example, photosystem 1 contains over three dozen proteins and many chlorophyll and other molecules which convert light energy into useful energy in the cell. “Antenna” molecules help increase the amount of light aborbed.96 Many complex molecules are necessary for this pathway to function properly.

41.Cellulosome complexes are intricate multi-enzyme machines produced by many cellulolytic microorganisms. They are designed for efficient degradation of plant cell wall polysaccharides, notably cellulose — the most abundant organic polymer on Earth.

More Cell Machines Come to Light 1

The living cell contains thousands of molecular machines converting energy into useful work. Here are just a few that were recently described in journal papers.
Any given week in the Proceedings of the National Academy of Sciences (PNAS), one is likely to find at least a dozen papers about molecular machines in the cell. Papers about biochemistry usually outnumber those in any other field of science. As imaging techniques continue to improve, the study of cellular machines has thrived, giving scientists better looks at the workings of the cell at higher magnification and finer resolution. This trend shows no sign of stopping.
Those who have seen the film Unlocking the Mystery of Life remember the bacterial flagellum—an outboard motor. They may also remember Jed Macosko saying that a cell has “thousands of machines.” Some of the better-known ones, like the rotary engine ATP synthase and the tightrope-walking dynein, may also be familiar. Let’s take a look at samples from this last week’s catalog of machines discussed in one journal, PNAS, to get a taste of the variety of equipment keeping every cell in operation.

The peroxide sensor (PNAS): Hydrogen peroxide, a powerful oxidant, can damage cells. Some types of bacteria have a special machine, OxyR, with four large domains, that sense H2O2 molecules. When a peroxide molecule is captured, one domain of the machine undergoes a “large conformational change” that triggers the regulatory domains into action.

Peroxisome splitter (PNAS): Peroxides, along other reactive oxygen species and long-chain fatty acids are disposed of in a molecular furnace called the peroxisome. This organelle, containing enzymes involved in many metabolic processes, is duplicated by fission, similar to cell division. A molecular scissors named Peroxin 11 is responsible for initiation of the process; the researchers discovered that it is also important for the final step, scission, producing the two daughter organelles. Interestingly, this machine is “conserved” [unevolved] from yeast to mammalians.”

The shape shifter (PNAS): These authors introduce their machine by saying, “Cells constantly sense and respond to mechanical signals by reorganizing their actin cytoskeleton.” They describe how a force applied to the cell membrane triggers a burst of calcium ions that, in turn, triggers actin molecules around the nucleus to reorganize the skeleton. The actin filaments form a “perinuclear rim” that “may function as a kinetic barrier to protect genome integrity until cellular homeostasis is reestablished.”

The volume control (PNAS): This machine is right in the back of your eyeballs. Retina pigment cells must control their volume; how do they do it? There’s a volume-activated anion channel (VRAC) able to respond to swelling by opening its gates to let out excess ions. When this machine breaks because of mutations, macular dystrophy can result.

Powerstroke of the walker (PNAS): This paper says, “Kinesin molecular motors couple ATP turnover to force production to generate microtubule-based movement and microtubule dynamics.” The authors discuss kinesin-14 from fruit flies, and show how its conversion of ATP to motion during the powerstroke is more complicated than thought. Then they say, “These findings are significant because they reveal that the key principles for force generation by kinesin-14s are conserved [i.e., unevolved] from yeast to higher eukaryotes.”

The thermostat (PNAS): A machine call DesK responds to temperature changes (“essential to cell survival”) by triggering a reversible “zipper” mechanism. In bacterial cells, the transmembrane machine switches its shape if the temperature rises on the outside, triggering additional motions on the inside that can switch on other machines that induce other molecular responses. “The reversible formation of a serine zipper represents a novel mechanism by which membrane-embedded sensors may detect and transmit signals.”

The tightrope walker (PNAS): The two-legged robot dynein walks on tightropes of microtubules, carrying cargo around the cell. Its feet (actually called “heads” by biochemists) have to be able to attach to the microtubules, but can switch from one rope to another as they move. This team investigated what happens when tension is applied to the machine. They dynein will slide if applied in one direction, but fasten more firmly in the other direction. This response is regulated by four additional machines (AAA1-4) that each use ATP as well.

The emergency squad (PNAS): One of the worst emergencies in a cell is when both strands of a DNA double helix snap; it can trigger death of the cell or serious malfunction, leading to disease or cancer. Cosmic rays, chemicals or failures in normal cell processes like transcription can cause double-stranded breaks. Fortunately, there’s an emergency response team named NHEJ (non-homologous end-joining) that knows what to do. The researchers used super-resolution microscopy to watch the team build long filaments at either side of the break as one step in the repair process.
A machine is a device that converts energy into work—not just any work, but directed, useful, functional work. The authors of these and many other papers have no hesitation calling these proteins “machines” and “motors.” Scientists have known about enzymes and proteins for well over a century, but understanding that cells operate with actual machines only dates back about 20 years or so. This revelation—that life operates by thousands of tiny mechanical devices—surely deserves to be called one of the most astounding discoveries in the history of science.

One might compare this discovery to zooming in on what happens when a building is built. Perhaps you’ve watched one of those time-lapse films of a construction project. From a distance, you see just the major features taking shape. If you had never seen such a process before, you might assume this is “just what happens” from time to time. Then, as you are given a series of telescopes with higher and higher resolution, with the ability to stop individual frames of the sequence, the true picture becomes increasingly clear. You find hundreds of people down there operating cranes, bulldozers, ropes, pulleys, ramps and trucks. As you zoom in closer, you see them working in squads, communicating with phones, shaking hands, pointing and responding to each other’s actions. Undoubtedly, your appreciation of what’s involved in construction of a building would grow dramatically.
Now shrink that down a billion-fold. Since the first humans opened their eyes and beheld the living world, there was plenty to show design. But we were like the viewer of the construction project from miles away, unaware of the actual way things work. People understood their bodies and the actions of animals or growth of plants at a macro level only: the running of a deer through a forest, the joy of eating good food and the necessity of disposing of waste, the act of sex and the birth of a child. When layers inside the body became exposed on the hunt, or through injury, a little more of the complexity would be apparent. But without detailed knowledge of what makes a heart beat, or what a liver or kidney actually does, these still might be taken for granted. Except for occasional insights from classical scholars like Aristotle, Hippocrates and Galen, the history of modern medicine and physiology only goes back a few centuries out of the thousands of years man has existed. Modern science starting the zoom-in view on the construction view. Leeuwenhoek opened the world’s eyes to the microbial world; he was astonished to see some of them dancing about with elegant motions.
Fast-forward to about 1995 to the present. We are privileged to live in an age of unprecedented discovery, where our view has zoomed in to the range of billionths of a meter. What did we find? Just fluids jostling about, undergoing chemical reactions? No! A thousand times no! We found machines at work in factories, interacting with incredible efficiency. We found libraries of digital code. We found machines reading the code, translating it, and converting it into other machines. We found thermostats, walking robots, rotary engines, emergency response squads, and long-distance communication networks. We found temperature sensors, volume sensors, disposal services, packaging services, and defense systems. Sex was no longer the transfer of a featureless fluid from the male to the female, but a process of unbelievable complexity involving swimming robots carrying gigabytes of information to be joined to a very complex egg cell with more gigabytes of information, triggering a cascade of machines building machines all the way to a complete baby. The growth of a seedling into a plant is no longer to be shrugged off as something that happens from time to time in nature, but a complex interplay of hormones triggering changes to thousands of molecular machines in plant cells. It’s a planet of machinery! Look around and consider how every living organism, from the worm in the soil, to the bee pollinating a flower, to the hummingbird in the garden, to the tree growing higher and higher in your back yard, operates through the action of thousands of molecular machines that we have begun to understand only in the last tenth of 1% of recorded human history.
If the wonder of what we have discovered doesn’t make you shout “Praise the Lord!” as never before, you might be asleep or dead.
Tragically, praise has been the last thing on the minds of many scientists studying these things. A century and a half of Darwinian dogma has blinded their minds to the obvious inference to intelligent design from molecular machines. We find, however, some curious things in these papers. One is the frequent use of “remarkable” by the authors when they uncover something wonderful. Another is the increasing silence about Darwinism as more details come to light. (There’s an inverse relationship between the frequency of evolution-words to the amount of detail in scientific papers about molecular machines.) A third curious thing is biomimetics: i.e., how cellular machines inspire thoughts of copying those designs for human applications. Together, these curiosities in PNAS and other journals hint that the consciences of evolutionary biologists are not completely dead. A flicker of the design inference still burns and may catch fire some day. When it does, it could burn away the Darwinian chaff, liberate philosophy to once again celebrate natural design as real and pervasive, and provide rational grounds for people of understanding in academia to shout unrestrained, “Great is the Lord, and greatly to be praised!”



1) http://crev.info/2015/05/cell-machines/

https://www.youtube.com/watch?v=dMPXu6GF18M




https://en.wikipedia.org/wiki/Molecular_machine

The most complex molecular machines are proteins found within cells. These include motor proteins, such as myosin, which is responsible for muscle contraction, kinesin, which moves cargo inside cells away from the nucleusalong microtubules, and dynein, which produces the axonemal beating of motile cilia and flagella. These proteins and their nanoscale dynamics are far more complex than any molecular machines that have yet been artificially constructed.
Probably the most significant biological machine known is the ribosome. Other important examples include ciliary mobility. A high-level-abstraction summary is that, "[i]n effect, the [motile cilium] is a nanomachine composed of perhaps over 600 proteins in molecular complexes, many of which also function independently as nanomachines."^[1] Flexible linker domains allow the connecting protein domains to recruit their binding partners and induce long-range allostery via protein domain dynamics. ^[5]
This protein flexibility allows the construction of biological machines. The first useful applications of these biological machines might be in nanomedicine. For example,^[6] they could be used to identify and destroy cancer cells.^[7][8]Molecular nanotechnology is a speculative subfield of nanotechnology regarding the possibility of engineering molecular assemblers, biological machines which could re-order matter at a molecular or atomic scale. Nanomedicine would make use of these nanorobots, introduced into the body, to repair or detect damages and infections. Molecular nanotechnology is highly theoretical, seeking to anticipate what inventions nanotechnology might yield and to propose an agenda for future inquiry. The proposed elements of molecular nanotechnology, such as molecular assemblers and nanorobots are far beyond current capabilities.^[9][10]

Molecular Machines

Putting the Pieces Together

http://jcb.rupress.org/content/152/1/F1.full

 It is now clear that most functions in the cell are not carried out by single protein enzymes, colliding randomly within the cellular jungle, but by macromolecular complexes containing multiple subunits with specific functions (Alberts 1998). Many of these complexes are described as “molecular machines.” Indeed, this designation captures many of the aspects characterizing these biological complexes: modularity, complexity, cyclic function, and, in most cases, the consumption of energy. Examples of such molecular machines are the replisome, the transcriptional machinery, the spliceosome, and the ribosome.

Molecular Machines Use Physics to Do Mechanical Work 1

One of the channels in the cell membrane that opens to let ions in turns out to act like a molecular spring. Phys.org includes an animated diagram of NOMPC (“nomp-see”) that works in a fly’s sense of touch and hearing. The channel is made up of four units that each appear to respond to mechanical pressure much like a spring. Researchers from the University of California, publishing their findings in Nature, believe that as the spring is compressed, the channel opens to let the ions flow. This would make sense, because to respond to touch, channels must be directly pulled or twisted open by microscopic forces somehow, but more work will be needed to actually witness the physics in action.

Mechanotransduction 6
Mechanotransduction is the process of converting physical forces into intracellular biochemical responses. The rebirth/change in view toward tissue engineering has made "mechanotransduction" a major buzzword in the field. Essentially, this term generally refers to the mechanical factors that influence cell behavior and differentiation. Stretch, substrate stiffness, loading (compressive, tensile, shear): these are all mechanical loads that are 'sensed' or felt by a cell and are converted into biochemical response such as up or down regulated expression of proteins, cell movement, and/or cell spreading. Ion channels, integrins which are connected to the cytoskeleton, growth factor receptors, cytoskeletal filaments, and even the nucleus of a cell are thought to be 'mechanically activated' and respond directly to, say, stretch of a cell. While exact pathways of converting mechanical stimulus into biochemical response varies among cell types (and even within a cell type) it has become clear that cells have a strong sense of their mechanical environment and respond to changes in this environment.

Electron cryo-microscopy structure of the mechanotransduction channel NOMPC 3
Mechanosensory transduction for senses such as proprioception, touch, balance, acceleration, hearing and pain relies on mechanotransduction channels, which convert mechanical stimuli into electrical signals in specialized sensory cells. How force gates mechanotransduction channels is a central question in the field, for which there are two major models. One is the membrane-tension model: force applied to the membrane generates a change in membrane tension that is sufficient to gate the channel, as in the bacterial MscL channel and certain eukaryotic potassium channels. The other is the tether model: force is transmitted via a tether to gate the channel. The transient receptor potential (TRP) channel NOMPC is important for mechanosensation-related behaviors such as locomotion, touch and sound sensation across different species including Caenorhabditis elegans, Drosophila and zebrafish. NOMPC is the founding member of the TRPN subfamily and is thought to be gated by tethering of its ankyrin repeat domain to microtubules of the cytoskeleton. Thus, a goal of studying NOMPC is to reveal the underlying mechanism of forceinduced gating, which could serve as a paradigm of the tether model. NOMPC fulfils all the criteria that apply to mechanotransduction channels and has 29 ankyrin repeats, the largest number among TRP channels. A key question is how the long ankyrin repeat domain is organized as a tether that can trigger channel gating. Here we present a de novo atomic structure of Drosophila NOMPC determined by single-particle electron cryo-microscopy. Structural analysis suggests that the ankyrin repeat domain of NOMPC resembles a helical spring, suggesting its role of linking mechanical displacement of the cytoskeleton to the opening of the channel. The NOMPC architecture underscores the basis of translating mechanical force into an electrical signal within a cell.




Molecular springs produce a fly's sense of touch and hearing 3

https://www.youtube.com/watch?v=IUmq68C_yrM


As senses go, there's nothing so immediate and concrete as our sense of touch. So it may come as a surprise that, on the molecular level, our sense of touch is still poorly understood.

Each of our senses relies on "receptor" molecules that turn signals like light, sound, and movement into electrical impulses for nerves to carry to the brain. Scientists have a fairly complete understanding of how receptors in the eye translate light into sight, and they've mapped many of the proteins in the nose and mouth that translate chemical signals into smell and taste.
But still mysterious are the "mechanoreceptors," which detect cells' motion to produce our senses of touch and hearing, and even pick up on our body's position and the flow of blood through our veins.
Now, UC San Francisco scientists have mapped in exquisite detail a protein complex called NOMPC (pronounced "nomp-see"), which acts as a mechanoreceptor in animals from fruit flies to fish and frogs. The structure, reported June 26, 2017 in Nature, reveals a machine that depends on a quartet of tiny springs that tether the complex to the cell's "skeleton" and react to its movement.
Though NOMPC is not found in mammals like us, the new structure gives scientists a better understanding of the subtle machinery that may allow our own sensory cells to detect touch.

In particular, the channels responsible for the human sense of hearing – which works by picking up subtle vibrations in the air – have thus far evaded detailed study. If, as some scientists hypothesize, a tethered receptor is responsible for our sense of hearing, it may well work much like NOMPC.

Springs Could Fine-Tune Channel's Sensitivity
The NOMPC receptor was mapped in such detail thanks to recent technological breakthroughs in a technique known as single particle electron cryo-microscopy.  NOMPC receptor was revealed as a bundle of four identical proteins that sits in a cell's membrane, each with a spring-like tether reaching into the cell.

The  receptor does not respond to movements in the membrane alone, but that larger movements in the cytoskeleton – the network of structural fibers that allow the cell to hold its shape – cause bundle to open up, forming a hole in the cell's membrane. Charged ions rush through the hole into the cell, creating an electrical impulse that signals touch to the nervous system.
Previously mapped touch receptors float free in the cell membrane, responding only when their particular patch of the cell's surface changes shape. But the new structural data show how NOMPC's spring-like tethers might tie it to the cytoskeleton, potentially enabling the receptor to sense distant changes in the cell's shape. Nature has created its own tiny spring to tie the receptor to the cytoskeleton."

Do You Pull It? Push It? Twist It?
To fully understand how channels like NOMPC open and close, scientists must observe the structure of the channels in both open and closed states. This is relatively easy for proteins that respond to light, like those in our retina, or to chemicals, like those in our nose and mouth, since they can be triggered remotely – by a beam of light or a chemical wash, respectively. But the proteins that coordinate the mechanical senses – like touch and hearing – must be directly pulled or twisted open by microscopic forces. This is challenging for scientists to do in a controlled way. "It's difficult to apply a directional force to all these individual molecules," said David Bulkley, a postdoc in the Cheng lab and the other lead author on the study. "And we don't know which direction will activate the channel – do you pull it, do you push it, do you twist it?" To work around this problem, the scientists are looking to find ways to force the channel open – perhaps by finding a molecule that binds to and locks open the protein, or by producing mutant versions of the protein which are stuck in the "open" position. In the meantime, the team is also working to generate computational models of the protein. The high-resolution structure they've obtained will help them simulate in detail what happens when the tethers are put under tension.

Gating prokaryotic mechanosensitive channels 4
Prokaryotic mechanosensitive channels function as molecular switches that transduce bilayer deformations into protein motion. These protein structural rearrangements generate large non-selective pores that function as a prokaryotic ‘last line of defense’ to sudden osmotic challenges. Once considered an electrophysiological artifact, recent structural, spectroscopic and functional data have placed this class of protein at the center of efforts to understand the molecular basis of lipid–protein interactions and their influence on protein function.

Life as a free-living unicellular organism is associated with a vulnerability to radical environmental changes. This life strategy also provides a constant selective pressure that drives the evolution of mechanisms to cope with the numerous inconveniences imposed by nature.

Question: How could the first life-forms have survived without these mechanisms to cope with the changing environmental conditions?  Had these mechanisms not to be fully developed to permit these life forms to adapt to the environment, right from the beginning?

Therefore, much of the prokaryotic genome encodes membrane-protein systems that help to regulate, for example, intracellular pH, the concentrations of all ions and many signaling molecules, the ability to pump toxic substances out of cells, and membrane fluidity in response to temperature changes. Particularly interesting physiological strategies relate to the control of cell volume and the associated responses to osmolarity changes. For a prokaryote, when the surrounding medium becomes hyperosmotic, water leaves the cell, which potentially increases the intracellular ionic strength and therefore affects the electrostatic balance that drives various cellular processes. The effects of hyperosmotic 5 environments are counterbalanced by the existence of transport mechanisms that help to accumulate a few specific osmolites (for example, proline) in cells, and so reduce the movement of water out of the cytoplasm by increasing solute concentrations. When the external environment becomes hypo-osmotic, water enters the cell, which increases membrane turgor and can potentially destroy the cell. This cellular emergency is usually defused by mechanosensitive channels. In response to changes in bilayer tension, these membrane proteins open to form large aqueous pores that allow the passage of both solute and solvent, and quickly equilibrate any hypo-osmotic imbalance4–9 (FIG. 1).



Because of the various modes of gating and the wide range of ionic selectivities, mechanosensitive channels have been classified according to their functional properties, and are therefore considered to be molecularly
heterogeneous. Some of these channels have been identified biochemically and cloned, including certain families of prokaryotic mechanosensitive channels that are found in both archaea and eubacteria. Eukaryotic
mechanosensitive channels have also been identified and cloned, and these belong to the degenerin/epithelial Na+ channel (DEG/ENaC) family and the transient receptor potential (TRP)-channel family (for example,
TRPA1, which was recently identified as the molecular determinant of mechanosensitivity in the cochlea;.



Prokaryotic mechanosensitive channels are gated through changes in bilayer tension (as are members of the eukaryotic two-pore-domain potassium K+channel family), whereas eukaryotic mechanosensitive channels usually respond to mechanical stimuli through their association with cytoskeletal elements. Nevertheless, the recent identification and cloning of the eukaryotic stretch-activated channel TRPC1 (also known as MscCa)17 showed
that bilayer-dependent mechanotransduction might be more common in eukaryotic systems than was previously thought.


1. https://evolutionnews.org/2017/07/molecular-machines-use-physics-to-do-mechanical-work/
2. http://www.nature.com.sci-hub.cc/nature/journal/v547/n7661/full/nature22981.html
3. https://phys.org/news/2017-07-molecular.html
4. http://www.nature.com.sci-hub.cc/nrm/journal/v7/n2/full/nrm1833.html
5. https://en.wikipedia.org/wiki/Osmotic_concentration
6. http://soft-matter.seas.harvard.edu/index.php/Mechanotransduction

Books:
1. Masahiro Kinoshita Mechanism of Functional Expression of the Molecular Machines,  SPRINGER BRIEFS IN MOLECULAR SCIENCE
2. Advances in Atom and Single Molecule Machines ;Single Molecular Machines and Motors: Proceedings of the 1st International Symposium on Single Molecular Machines and Motors, Toulouse 19-20 June 2013
3. Molecular Machines and Motors Editors Recent Advances and Perspectives 2014
4. Molecular machines involved in peroxisome biogenesis and maintenance 2014
5. MOLECULAR MACHINES IN BIOLOGY Workshop of the Cell Edited by Joachim Frank Columbia University

Science papers:
1.“Biological machines: from mills to molecules,” Nature Reviews Molecular Cell Biology, Vol. 1:149-153 (November, 2000).
2.Thomas Köcher & Giulio Superti-Furga, "Mass spectrometry-based functional proteomics: from molecular machines to protein networks," Nature Methods (October, 2007).
3."Crystalline Molecular Machines: A Quest Toward Solid-State Dynamics and Function," Accounts of Chemical Research, Vol. 39(6):413-422 (2006).
4."Molecular Machines," Annual Review of Biomedical Engineering, Vol. 6:363-395 (2004).
5."The Closest Look Ever At The Cell's Machines,” ScienceDaily.com (January 24, 2006).
6."The Cell as a Collection of Protein Machines: Preparing the Next Generation of Molecular Biologists," Cell, Vol. 92:291 (February 6, 1998).
7.Walter Neupert, "Highlight: Molecular Machines," Biological Chemistry, Vol. 386:711(August, 2005).
8.Seiji Kojima and David F. Blair, “The Bacterial Flagellar Motor: Structure and Function of a Complex Molecular Machine,” International Review of Cytology, Vol. 233:93-134 (2004).
9.Hugo ten Cate, “The blood coagulation system as a molecular machine,” BioEssays, Vol. 25:1220-1228 (2003).
10.John L Woolford, Jr, “Assembly of ribosomes and spliceosomes: complex ribonucleoprotein machines,” Current Opinion in Cell Biology, Vol. 21(1):109-118 (February, 2009).
11.Reinhard Lührmann, "The Spliceosome: Design Principles of a Dynamic RNP Machine," Cell, Vol. 136: 701-718 (February 20, 2009).
12.Timothy W. Nilsen, "The spliceosome: the most complex macromolecular machine in the cell?," BioEssays, Vol. 25:1147-1149 (2003).
13.L. Yarmush, "Molecular Machines," Annual Review of Biomedical Engineering, Vol. 6:363-395 (2004);
14.Paul D. Boyer, "The ATP Synthase--A Splendid Molecular Machine," Vol. 66:717-749 (1997);
15.Steven M. Block, "Real engines of creation," Nature, Vol. 386:217-219 (March 20, 1997).
16.C. Mavroidis, A. Dubey, and M.L. Yarmush, "Molecular Machines," Annual Review of Biomedical Engineering, Vol. 6:363-395 (2004)
17.Ronald D. Vale, “The Molecular Motor Toolbox for Intracellular Transport,” Cell, Vol. 112:467-480 (February 21, 2003).
18.Sharyn A. Endow, “Kinesin motors as molecular machines,” BioEssays, Vol. 25:1212-1219 (2003).
19.Michiel Meijer, “Mitochondrial biogenesis: The Tom and Tim machine,” Current Biology, Vol. 7:R100-R103 (1997).
20.Maurizio Brunori, "Structure and function of a molecular machine: cytochrome c oxidase," Biophysical Chemistry, Vol. 54: 1-33 (1995).
21.Robert T. Sauer, “Structures of Asymmetric ClpX Hexamers Reveal Nucleotide-Dependent Motions in a AAA+ Protein-Unfolding Machine,” Cell, Vol. 139:744-756 (November 13, 2009).
22.Michael L. Dustin, “The Immunological Synapse: A Molecular Machine Controlling T Cell Activation,” Science, Vol. 285:221-227 (July 9, 1999).
23.Dominique Soldati, ”The glideosome: a molecular machine powering motility and host-cell invasion by Apicomplexa,” Trends in Cell Biology, Vol.14(10): 528-532 (October, 2004).
24.Arthur L. Horwich, “The Hsp70 and Hsp60 Chaperone Machines,” Cell, Vol. 92: 351-366 (February 6, 1998).
25.Tobias Meyer, “Protein Kinase C as a Molecular Machine for Decoding Calcium and Diacylglycerol Signals,” Cell, Vol. 95:307–318 (October 30, 1998).
26.Venigalla B. Rao, “The Structure of the Phage T4 DNA Packaging Motor Suggests a Mechanism Dependent on Electrostatic Forces,” Cell, Vol. 135:1251-1262 (December 26, 2008).
27.M.L. Yarmush, “Molecular Machines,” Annual Review of Biomedical Engineering, Vol. 6:363-395 (2004).
28.“The Molecular Motor Toolbox for Intracellular Transport,” Cell, Vol. 112:467-480 (February 21, 2003).
29.E. Karsenti and I. Vernos, "The Mitotic Spindle: A Self-Made Machine," Science, Vol. 294:543-547 (October 19, 2001);
30.Mike O’Donnell, "The internal workings of a DNA polymerase clamp-loading machine," The EMBO Journal, Vol.18:771-783 (1999); “DNA Polymerase: an Active Machine,” The Journal of Biological Chemistry, Vol. 282:e99940 (September 28, 2007).
31.Mike O’Donnell, "The internal workings of a DNA polymerase clamp-loading machine," The EMBO Journal, Vol.18:771-783 (1999).
32.Terence Strick, RNA polymerases as molecular motors , p. 304 (Royal Society of Chemistry, 2009).
33.Martin Renatus, “Apoptosome: The Seven-Spoked Death Machine,” Developmental Cell, Vol. 2(3): 256-257 (March 1, 2002).
34.Alan Collmer, “Type III Secretion Machines: Bacterial Devices for Protein Delivery into Host Cells,” Science, Vol. 284:1322-1328 (May 21, 1999).
35.Agamemnon J. Carpousis, “The RNA Degradosome of Escherichia coli: An mRNA-Degrading Machine Assembled on RNase E,” Annual Review of Microbiology, Vol. 61:71-87 (October 2007).

The ur-metaphor of all of modern science, the machine model that we owe to Descartes, has ceased to be a metaphor and has become the unquestioned reality: Organisms are no longer like machines, they are machines.’ (Lewontin, 1996, p. 1)


The machine conception of the organism (MCO) is one of the most pervasive notions in modern biology. 1




1. https://philarchive.org/archive/NICO

Molecular Machines point to intelligent design

https://reasonandscience.catsboard.com/t1289-molecular-machines-in-biology#7492

1. Living cells are full of Molecular machines, rotors, and engines, and they are made upon the same design principles as big machines. They are a pre-requisite for DNA replication. Life, according to a science paper from 2016,  needs a minimum of 438 different, in part interdependent proteins in order to start, and they require to be fully in place before natural selection can be considered as a driving force to produce evolutionary novelties.

2. The emergence of machines for specific purposes, and assembly lines of machines working in a joint venture, have never been observed to emerge by lucky accidents, spontaneously through self-organization by unguided natural events in an orderly manner without external direction,  purely physicodynamic processes, and reactions, but always through the direct intervention and creative force of an intelligent agency, a powerful creator.

3. Therefore, the origin of molecular machines is best explained by the ( past )creative act of an intelligent designer.

1. Bacterial Flagellum: is a rotary motor in bacteria that drives a propeller to spin, much like an outboard motor, powered by ion flow to drive rotary motion.
2. Eukaryotic Cilium: The cilium is a hair-like, or whip-like structure that is built upon a system of microtubules, typically with nine outer microtubule pairs and two inner microtubules.
3. Aminoacyl-tRNA Synthetases (aaRS): are responsible for charging tRNAs with the proper amino acid so they can accurately participate in the process of translation.
4. The blood coagulation system:  “is a typical example of a molecular machine, where the assembly of substrates, enzymes, protein cofactors etc.accelerate the rate of coagulation.”
5. Ribosome:  is an “RNA machine” that “involves more than 300 proteins and RNAs” to form a complex where messenger RNA is translated into protein.
6. Antibodies and the Adaptive Immune System:  are “the ‘fingers’ of the blind immune system—they allow it to distinguish a foreign invader from the body itself.”
7. Spliceosome:  removes introns from RNA transcripts prior to translation.
8. F0F1 ATP Synthase: According to cell biologist and molecular machine modeler David Goodsell, “ATP synthase is one of the wonders of the molecular world.”
9. Bacteriorhdopsin:  “is a compact molecular machine” uses that sunlight energy to pump protons across a membrane.
10. Myosin:  is a molecular motor that moves along a “track”—in this case actin filaments—to form the basis of muscle movement or to transport cargoes within the cell.
11. Kinesin Motor: Much like myosin, kinesin is a protein machine that binds to and carries cargoes by “crawls hand-over-hand along a microtubule” in the cell.
12. Tim/Tom Systems are selective protein pump machines that import proteins across the inner (Tim) and outer (Tom) membranes of mitochondria into the interior matrix of the mitochondria.
13. Calcium Pump: The calcium pump is an “amazing machine with several moving parts“ that transfers calcium ions across the cell membrane.
14. Cytochrome C Oxidase: Cytochrome C Oxidase qualifies as a molecular machine “since part of the redox free energy is transduced into a proton electrochemical gradient.”
15. Proteosome:  is a large molecular machine whose parts must be must be carefully assembled in a particular order.
16. Cohesin: Cohesin is molecular machine “multisubunit protein complex"52 and “a macromolecular complex that links sister chromatids together at the metaphase plate during mitosis.”
17. Condensin is a molecular machine that helps to condense and package chromosomes for cell replication. It is a five subunit complex, and is “the key molecular machine of chromosome condensation.”
18. ClpX:  is a molecular machine that uses ATP to both unfold proteins and then transport unfolded proteins into another complex in the cell. It moves these proteins into the ClpP complex.
19. Immunological Synapse:  is a molecular machine that serves as an interface to activate of T cells.
20. Glideosome:  is a “macromolecular complex” and an “elaborate machine”57 whose function is to allow protozoa to rely on gliding motility over various substrates.
21. Kex2: is a molecular machine that facilitates cell fusion during the mating of yeast; it likely works by degrading cell walls.
22. Hsp70 is one of many molecular machines that serve as chaperones that not only assist other proteins in reaching a proper functional conformation (i.e. proper folding)
23. Hsp60 is another chaperone machine – it is tailored to provide “an enclosed environment for folding proteins which totally protects them as they fold.”
24. Protein Kinase C:  is a molecular machine that is activated by certain calcium and diacylglycerol signals in the cell.
25. SecYEG PreProtein Translocation Channel is vital to the operation of “translocation machinery” which works to move molecules across membranes in the cell.
26. Hemoglobin: Molecular machine modeller David Goodsell observes that “Hemoglobin is a remarkable molecular machine that uses motion and small structural changes to regulate its action.”
27. T4 DNA Packaging Motor is one of various packaging motors that are “powerful molecular motors” which emplace viral genomes into capsules called procapsids.
28. Smc5/Smc6 is a complex machine that is involved with the structural maintenance of chromosomes with regards to cohesions and condensins
29. Cytplasmic Dynein is a machine involved with cargo transport and movement cell that functions like a motor with a “power stroke.”
30. Mitotic Spindle Machine is a highly dynamic self-assembling complex molecular machine composed of tubulin, motors, and other molecules
31. DNA Polymerase is a multiprotein machine that creates a complementary strand of DNA from a template strand.
32. RNA Polymerase: Like its DNA polymerase counterpart, the function of the RNA polymerase is to create a messenger RNA strand from a DNA template strand.
33. Kinetochore: The kinetochore is a “proteinaceous structure that assembles on centromeric chromatin and connects the centromere to spindle microtubules.”
34. MRX Complex forms telomere length counting machinery that measures the integrity of telomeres, the structures that protect the ends of eukaryotic chromosomes.
35. Apoptosome / Caspase: While many molecular machines keep a cell alive, there are even machines that are programmed to cause cell death, or apoptosis.
36. Type III Secretory System: This machine, often called the T3SS, is a toxin injection machine used by predatory bacteria to deliver deadly toxins into other cells.
37. Type II Secretion Apparatus: The T2SS is a complex nanomachine that translocates proteins across the outer membrane of a bacterium.89
38. Helicase/Topoisomerase Machine work together to properly unwrap or unzip DNA prior to transcription of DNA into mRNA or DNA replication.
39. RNA degradasome “multiprotein complex involved in the degradation of mRNA” or trimming RNAs into their active forms in E. coli bacteria.
40. Photosynthetic system: The processes that plants use to convert light into chemical energy a type of molecular machines.e amount of light aborbed.



https://www.mcgill.ca/newsroom/channels/news/how-map-cell-signaling-molecules-their-targets-230355
Cyclin-dependent kinase 1 (Cdk1), the so-called master regulator of the cell cycle machinery, essential for cell division, and drives cells through G2 phase and mitosis, and is, as such of fundamental importance.

1. Bacterial Flagellum: is a rotary motor in bacteria that drives a propeller to spin, much like an outboard motor, powered by ion flow to drive rotary motion. Flagellum, Behe's prime example of irreducible complexity
https://reasonandscience.catsboard.com/t1528-the-flagellum-behe-s-prime-example-of-irreducible-complexity

2. Eukaryotic Cilium: The cilium is a hair-like, or whip-like structure that is built upon a system of microtubules, typically with nine outer microtubule pairs and two inner microtubules.
The remarkable intraflagellar transport for Flagellum assembly
https://reasonandscience.catsboard.com/t2642-the-remarkable-intraflagellar-transport-for-flagellum-assembly

3. Aminoacyl-tRNA Synthetases (aaRS): are responsible for charging tRNAs with the proper amino acid so they can accurately participate in the process of translation.
Aminoacyl-tRNA synthetases point to design
https://reasonandscience.catsboard.com/t2280-aminoacyl-trna-synthetases

4. The blood coagulation system:  “is a typical example of a molecular machine, where the assembly of substrates, enzymes, protein cofactors etc.accelerate the rate of coagulation.”
Hematopoiesis. The mystery of blood Cell and vascular Formation
https://reasonandscience.catsboard.com/t2295-hematopoiesis-the-mystery-of-blood-cell-and-vascular-formation

5. Ribosome:  is an “RNA machine” that “involves more than 300 proteins and RNAs” to form a complex where messenger RNA is translated into protein.
Ribosomes amazing nano machines
https://reasonandscience.catsboard.com/t1661-translation-through-ribosomes-amazing-nano-machines

6. Antibodies and the Adaptive Immune System:  are “the ‘fingers’ of the blind immune system—they allow it to distinguish a foreign invader from the body itself.”
The immune system, and irreducible complexity
https://reasonandscience.catsboard.com/t2322-the-immune-system-and-irreducible-complexity

7. Spliceosome:  removes introns from RNA transcripts prior to translation.
The awe inspiring spliceosome, the most complex macromolecular machine known, and pre-mRNA processing in eukaryotic cells
https://reasonandscience.catsboard.com/t2180-the-spliceosome-the-splicing-code-and-pre-mrna-processing-in-eukaryotic-cells

8. F0F1 ATP Synthase: According to cell biologist and molecular machine modeler David Goodsell, “ATP synthase is one of the wonders of the molecular world.”
The irreducibly complex ATP Synthase nanomachine, amazing evidence of design
https://reasonandscience.catsboard.com/t1439-the-irreducibly-complex-atp-synthase-nanomachine-amazing-evidence-of-design

9. Bacteriorhdopsin:  “is a compact molecular machine” uses that sunlight energy to pump protons across a membrane.
Origin of eyespots - supposedly one of the simplest eyes
https://reasonandscience.catsboard.com/t2638-volvox-eyespots-and-interdependence#5768

10. Myosin:  is a molecular motor that moves along a “track”—in this case actin filaments—to form the basis of muscle movement or to transport cargoes within the cell.
Kinesin and myosin motor proteins - amazing cargo carriers in the cell
https://reasonandscience.catsboard.com/t1448-kinesin-and-myosin-motor-proteins-amazing-cargo-carriers-in-the-cell

11. Kinesin Motor: Much like myosin, kinesin is a protein machine that binds to and carries cargoes by “crawls hand-over-hand along a microtubule” in the cell.
Kinesin and myosin motor proteins - amazing cargo carriers in the cell
https://reasonandscience.catsboard.com/t1448-kinesin-and-myosin-motor-proteins-amazing-cargo-carriers-in-the-cell

12. Tim/Tom Systems are selective protein pump machines that import proteins across the inner (Tim) and outer (Tom) membranes of mitochondria into the interior matrix of the mitochondria.
PROTEIN IMPORT INTO CHLOROPLASTS
https://reasonandscience.catsboard.com/t1303-challenges-to-endosymbiotic-theory#1841

13. Calcium Pump: The calcium pump is an “amazing machine with several moving parts“ that transfers calcium ions across the cell membrane.
How  intracellular Calcium signaling,  gradient and its role as a universal intracellular regulator points to design
https://reasonandscience.catsboard.com/t2448-howintracellular-calcium-signaling-gradient-and-its-role-as-a-universal-intracellular-regulator-points-to-design

14. Cytochrome C Oxidase: Cytochrome C Oxidase qualifies as a molecular machine “since part of the redox free energy is transduced into a proton electrochemical gradient.”
Cytochrome c reductase and oxydase
https://reasonandscience.catsboard.com/t2152-cytochrome-c-reductase-and-oxydase

15. Proteosome:  is a large molecular machine whose parts must be must be carefully assembled in a particular order.
Proteasome Garbage Grinders, evidence of luck, evolution, or design?
https://reasonandscience.catsboard.com/t1851-proteasome-garbage-grinders

16. Cohesin: Cohesin is molecular machine “multisubunit protein complex"52 and “a macromolecular complex that links sister chromatids together at the metaphase plate during mitosis.”
Cellular reproduction: Mitosis
https://reasonandscience.catsboard.com/t1992-mitosis-and-cell-division

17. Condensin is a molecular machine that helps to condense and package chromosomes for cell replication. It is a five subunit complex, and is “the key molecular machine of chromosome condensation.”
Cellular reproduction: Mitosis
https://reasonandscience.catsboard.com/t1992-mitosis-and-cell-division

18. ClpX:  is a molecular machine that uses ATP to both unfold proteins and then transport unfolded proteins into another complex in the cell. It moves these proteins into the ClpP complex.
19. Immunological Synapse:  is a molecular machine that serves as an interface to activate of T cells.
20. Glideosome:  is a “macromolecular complex” and an “elaborate machine”57 whose function is to allow protozoa to rely on gliding motility over various substrates.
21. Kex2: is a molecular machine that facilitates cell fusion during the mating of yeast; it likely works by degrading cell walls.
22. Hsp70 is one of many molecular machines that serve as chaperones that not only assist other proteins in reaching a proper functional conformation (i.e. proper folding)
Molecular Chaperones Help Guide the Folding of Most Proteins
https://reasonandscience.catsboard.com/t1437-chaperones

23. Hsp60 is another chaperone machine – it is tailored to provide “an enclosed environment for folding proteins which totally protects them as they fold.”
Molecular Chaperones Help Guide the Folding of Most Proteins
https://reasonandscience.catsboard.com/t1437-chaperones

24. Protein Kinase C:  is a molecular machine that is activated by certain calcium and diacylglycerol signals in the cell.
Receptor tyrosine kinase (RTK)
https://reasonandscience.catsboard.com/t2353-receptor-tyrosine-kinase-rtk

25. SecYEG PreProtein Translocation Channel is vital to the operation of “translocation machinery” which works to move molecules across membranes in the cell.
26. Hemoglobin: Molecular machine modeller David Goodsell observes that “Hemoglobin is a remarkable molecular machine that uses motion and small structural changes to regulate its action.”
THE AMAZING HEMOGLOBIN MOLECULE
https://reasonandscience.catsboard.com/t1322-the-amazing-hemoglobin-molecule

27. T4 DNA Packaging Motor is one of various packaging motors that are “powerful molecular motors” which emplace viral genomes into capsules called procapsids.
The amazing design of the DNA packaging motor
https://reasonandscience.catsboard.com/t2134-the-amazing-design-of-bacteriophage-viruses-and-its-dna-packaging-motor

28. Smc5/Smc6 is a complex machine that is involved with the structural maintenance of chromosomes with regards to cohesions and condensins
29. Cytplasmic Dynein is a machine involved with cargo transport and movement cell that functions like a motor with a “power stroke.”
30. Mitotic Spindle Machine is a highly dynamic self-assembling complex molecular machine composed of tubulin, motors, and other molecules
The Mitotic spindle , amazing evidence of design
https://reasonandscience.catsboard.com/t2483-the-mitotic-spindle-amazing-evidence-of-design

31. DNA Polymerase is a multiprotein machine that creates a complementary strand of DNA from a template strand.
DNA replication, and its mind boggling nano technology that defies naturalistic explanations
https://reasonandscience.catsboard.com/t1849-dna-replication-of-prokaryotes

32. RNA Polymerase: Like its DNA polymerase counterpart, the function of the RNA polymerase is to create a messenger RNA strand from a DNA template strand.
The complexity of transcription through RNA polymerase enzymes and general transcription factors in eukaryotes
https://reasonandscience.catsboard.com/t2036-the-complexity-of-transcription-through-rna-polymerase-enzymes-and-general-transcription-factors-in-eukaryotes

33. Kinetochore: The kinetochore is a “proteinaceous structure that assembles on centromeric chromatin and connects the centromere to spindle microtubules.”
Subunit organization in the Dam1 kinetochore complex and its ring around microtubules
https://reasonandscience.catsboard.com/t2107-subunit-organization-in-the-dam1-kinetochore-complex-and-its-ring-around-microtubules

34. MRX Complex forms telomere length counting machinery that measures the integrity of telomeres, the structures that protect the ends of eukaryotic chromosomes.
35. Apoptosome / Caspase: While many molecular machines keep a cell alive, there are even machines that are programmed to cause cell death, or apoptosis.
Apoptosis, Cell's essential mechanism of programmed suicide points to design
https://reasonandscience.catsboard.com/t2193-apoptosis-cell-s-essential-mechanism-of-programmed-suicide-points-to-design

36. Type III Secretory System: This machine, often called the T3SS, is a toxin injection machine used by predatory bacteria to deliver deadly toxins into other cells.
Flagellum, Behe's prime example of irreducible complexity
https://reasonandscience.catsboard.com/t1528-the-flagellum-behe-s-prime-example-of-irreducible-complexity

37. Type II Secretion Apparatus: The T2SS is a complex nanomachine that translocates proteins across the outer membrane of a bacterium.89
Flagellum, Behe's prime example of irreducible complexity
https://reasonandscience.catsboard.com/t1528-the-flagellum-behe-s-prime-example-of-irreducible-complexity

38. Helicase/Topoisomerase Machine work together to properly unwrap or unzip DNA prior to transcription of DNA into mRNA or DNA replication.
Hexameric helicases some of the most complex machines on Earth
https://reasonandscience.catsboard.com/t1438-hexameric-helicases-some-of-the-most-complex-machines-on-earth

39. RNA degradasome “multiprotein complex involved in the degradation of mRNA” or trimming RNAs into their active forms in E. coli bacteria.
40. Photosynthetic system: The processes that plants use to convert light into chemical energy a type of molecular machines.e amount of light aborbed.
Main topics on photosynthesis
https://reasonandscience.catsboard.com/t2629-main-topics-on-photosynthesis

Machines, robots, fully automated manufacturing production lines, transport carriers, turbines, transistors, computers, and factories are always set up by intelligent designers
Science has discovered, that cells are literally chemical nano factories, that operate based on molecular machines, protein robots, kinesin protein carriers, autonomous self-regulated production lines, generate energy through turbines, neuron transistors, and computers
Therefore, most probably, Cell factories containing all those things are the product of an intelligent designer.

https://reasonandscience.catsboard.com/t2809-analogy-viewed-from-science#7675

Molecular machines
https://reasonandscience.catsboard.com/t1289-molecular-machines-in-biology

https://en.wikipedia.org/wiki/Molecular_machine

Science papers:
1.“Biological machines: from mills to molecules,” Nature Reviews Molecular Cell Biology, Vol. 1:149-153 (November, 2000).
2.Thomas Köcher & Giulio Superti-Furga, "Mass spectrometry-based functional proteomics: from molecular machines to protein networks," Nature Methods (October, 2007).
3."Crystalline Molecular Machines: A Quest Toward Solid-State Dynamics and Function," Accounts of Chemical Research, Vol. 39(6):413-422 (2006).
4."Molecular Machines," Annual Review of Biomedical Engineering, Vol. 6:363-395 (2004).
5."The Closest Look Ever At The Cell's Machines,” ScienceDaily.com (January 24, 2006).
6."The Cell as a Collection of Protein Machines: Preparing the Next Generation of Molecular Biologists," Cell, Vol. 92:291 (February 6, 1998).
7.Walter Neupert, "Highlight: Molecular Machines," Biological Chemistry, Vol. 386:711(August, 2005).
8.Seiji Kojima and David F. Blair, “The Bacterial Flagellar Motor: Structure and Function of a Complex Molecular Machine,” International Review of Cytology, Vol. 233:93-134 (2004).
9.Hugo ten Cate, “The blood coagulation system as a molecular machine,” BioEssays, Vol. 25:1220-1228 (2003).
10.John L Woolford, Jr, “Assembly of ribosomes and spliceosomes: complex ribonucleoprotein machines,” Current Opinion in Cell Biology, Vol. 21(1):109-118 (February, 2009).
11.Reinhard Lührmann, "The Spliceosome: Design Principles of a Dynamic RNP Machine," Cell, Vol. 136: 701-718 (February 20, 2009).
12.Timothy W. Nilsen, "The spliceosome: the most complex macromolecular machine in the cell?," BioEssays, Vol. 25:1147-1149 (2003).
13.L. Yarmush, "Molecular Machines," Annual Review of Biomedical Engineering, Vol. 6:363-395 (2004);
14.Paul D. Boyer, "The ATP Synthase--A Splendid Molecular Machine," Vol. 66:717-749 (1997);
15.Steven M. Block, "Real engines of creation," Nature, Vol. 386:217-219 (March 20, 1997).
16.C. Mavroidis, A. Dubey, and M.L. Yarmush, "Molecular Machines," Annual Review of Biomedical Engineering, Vol. 6:363-395 (2004)
17.Ronald D. Vale, “The Molecular Motor Toolbox for Intracellular Transport,” Cell, Vol. 112:467-480 (February 21, 2003).
18.Sharyn A. Endow, “Kinesin motors as molecular machines,” BioEssays, Vol. 25:1212-1219 (2003).
19.Michiel Meijer, “Mitochondrial biogenesis: The Tom and Tim machine,” Current Biology, Vol. 7:R100-R103 (1997).
20.Maurizio Brunori, "Structure and function of a molecular machine: cytochrome c oxidase," Biophysical Chemistry, Vol. 54: 1-33 (1995).
21.Robert T. Sauer, “Structures of Asymmetric ClpX Hexamers Reveal Nucleotide-Dependent Motions in a AAA+ Protein-Unfolding Machine,” Cell, Vol. 139:744-756 (November 13, 2009).

Proteins are robots

Nature's robots: A history of proteins: Tanford, C., Reynolds, J
Shape-shifting molecular robots respond to DNA signals
When Nature's Robots Go Rogue: Exploring Protein ...
- Document - Nature's Robots: a History of Proteins - Gale
Bio-Inspired Self-Organizing Robotic Systems
GACR - Proteins - Multi-robot Systems
Buy Nature's Robots: A History of Proteins Book Online at Low ...

Molecular production lines

A molecular production line | Nature Chemistry
molecular assembly line | News and features
The molecular biology of production cell lines. - NCBI
Cell-Like 'Molecular Assembly Lines' of ... - Cordis
Biologically inspired molecular assembly lines - MIT Media Lab
DNA-based assembly lines and nanofactories


Cell factories
https://reasonandscience.catsboard.com/t2245-abiogenesis-the-factory-maker-argument

Microbial cell factory is an approach to bioengineering  which considers microbial  cells as a production facility in which the optimization process largely depends on metabolic engineering
https://en.wikipedia.org/wiki/Microbial_cell_factory

Science papers:
The Molecular Fabric of Cells  BIOTOL, B.C. Currell and R C.E Dam-Mieras (Auth.)
Plant Cells as Chemical Factories: Control and Recovery of Valuable Products
Fine Tuning our Cellular Factories: Sirtuins in Mitochondrial Biology
Cells As Molecular Factories
Eukaryotic cells are molecular factories in two senses: cells produce molecules and cells are made up of molecules.
Ribosome: Lessons of a molecular factory construction
Nucleolus: the ribosome factory
Ribosome: The cell city's factories
The Cell's Protein Factory in Action
What looks like a jumble of rubber bands and twisty ties is the ribosome, the cellular protein factory.
Chloroplasts are the microscopic factories on which all life on Earth is based.
Visualization of the active expression site locus by tagging with green fluorescent protein shows that it is specifically located at this unique pol I transcriptional factory.
There are millions of protein factories in every cell. Surprise, they’re not all the same
Rough ER is also a membrane factory for the cell; it grows in place by adding membrane proteins and phospholipids to its own membrane.
Endoplasmic reticulum: Scientists image 'parking garage' helix structure in protein-making factory
Theoretical biologists at Los Alamos National Laboratory have used a New Mexico supercomputer to aid an international research team in untangling another mystery related to ribosomes -- those enigmatic jumbles of molecules that are the protein factories of living cells.
The molecular factory that translates the information from RNA to proteins is called the "ribosome"
Quality control in the endoplasmic reticulum protein factory
The endoplasmic reticulum (ER) is a factory where secretory proteins are manufactured, and where stringent quality-control systems ensure that only correctly folded proteins are sent to their final destinations. The changing needs of the ER factory are monitored by integrated signalling pathways that constantly adjust the levels of folding assistants.
Molecular factories: The combination between nature and chemistry is functional


The brain is a " Uber-Computer "
https://reasonandscience.catsboard.com/t2734-the-brain-is-a-uber-computer-far-more-sophisticated-that-man-made-computers

The Cell is a super computer
https://reasonandscience.catsboard.com/t2712-the-cell-is-a-super-computer?highlight=computer

Your Cortex Contains 17 Billion Computers
Yes, the brain is a computer…
An 83,000-Processor Supercomputer Can Only Match 1% of Your Brain
Why cells are like computers—And how ‘hacking’ them could lead to new diagnostic tools
Hidden Computational Power Found in the Arms of Neurons
Dendritic action potentials and computation in human layer 2/3 cortical neurons
Single neuron dynamics and computation
What can a single neuron compute?
Brain-Inspired Computing Could Lead to Better Neuroscience

Neurons are transistors

Synaptic transistor
https://en.wikipedia.org/wiki/Synaptic_transistor

Neuron transistor behaves like a brain neuron - Phys.org
Digital: From Neurons to Transistors - LinkedIn
Capacitive neural network with neuro-transistors | Nature
A neuron-astrocyte transistor-like model for neuromorphic dressed neurons.
Electrolyte-gated organic synapse transistor interfaced ... - arXiv



Nature's robots, , a history of proteins

Robots already exist in nature and are called proteins!
https://medium.com/intuition/robots-already-exist-in-nature-and-are-called-proteins-2a3d99096743

Machine operates with atomic precision"

The adaptive immune system fights back unwanted invaders through highly sophisticated defense mechanisms. One of the central hinges of human adaptive immunity is the major histocompatibility complex (MHC) class I antigen presentation pathway. It loads pathogen-derived peptides onto MHC-I molecules in the endoplasmic reticulum (ER). This task is accomplished by the MHC class I peptide-loading complex (PLC), of which the transporter associated with antigen-processing (TAP) is a central component. 4

"Cells that are infected by a virus or carry a carcinogenic mutation, for example, produce proteins foreign to the body. Antigenic peptides resulting from the degradation of these exogenous proteins inside the cell are loaded by the peptide-loading complex onto so-called major histocompatibility complex molecules (MHC for short) and presented on the cell surface. There, they are specifically identified by T-killer cells, which ultimately leads to the elimination of the infected cells. This is how our immune system defends us against pathogens."

The peptide-loading complex is a biological nanomachine that has to work with atomic precision in order to efficiently protect us against pathogens that cause disease.

A nanomachine, the MHC, with 1,6 million atoms...all exactly located in the precise place to do their job; identifying "foreign" protein fragments and setting them up for t-cells to eliminate, exists in every cell of our body. 1

Our body constantly encounters pathogens or malignant transformation. Consequently, the adaptive immune system is in place to eliminate infected or cancerous cells.

Intracellular transport, loading, and editing of antigenic peptides onto MHC-I are coordinated by a highly dynamic multisubunit peptide-loading complex (PLC) in the endoplasmic reticulum ER membrane. This multitasking machinery orchestrates the translocation of proteasomal degradation products into the ER as well as the loading and proofreading of MHC-I molecules.
Sampling of myriads of different peptide/MHC-I allomorphs requires a precisely coordinated quality control network in a single macromolecular assembly, including the transporter associated with antigen processing TAP1/2, the MHC-I heterodimer, the oxidoreductase ERp57, and the ER chaperones tapasin and calreticulin. Proofreading by MHC-I editing complexes guarantees that only very stable peptide/MHC-I complexes are released to the cell surface. 3 


Atomistic structure and dynamics of the human MHC-I peptide-loading complex
The major histocompatibility complex class-I (MHC-I) peptideloading complex (PLC) translocates cytosolic degradation products to the endoplasmic reticulum to load antigenic peptides onto MHC-I molecules. Stable peptide–MHC-I complexes are presented at the cell surface to mirror cellular contents for patrolling T cells, which protect against viral infections and cancer-causing mutations by inducing apoptosis in cells that expose nonself peptides. 

"the simulated system is extremely large with its 1.6 million atoms"

The major histocompatibility complex class-I (MHC-I) peptideloading complex (PLC) is a cornerstone of the human adaptive immune system, being responsible for processing antigens that allow killer T cells to distinguish between healthy and compromised cells.  (1.6 million atoms in total). The PLC has a layered structure, with two editing modules forming a flexible protein belt surrounding a stable, catalytically active core. 


To protect us against cancer and intracellular pathogens, the human adaptive immune system relies on a signaling mechanism whereby antigens are exposed at the surface of cells by major histocompatibility complex class-I (MHC-I) proteins for recognition by killer T cells.  These antigens are, or the most part, short peptides (8 to 12 amino acids) resulting from the degradation of intracellular proteins. Peptides exposed at the cell surface by MHC-I, therefore, mirror cellular contents: In healthy cells, only peptides from the “self” are exposed; in cells compromised by a virus or cancer-causing mutation, both self and “nonself” peptides, either viral or mutated, are exposed. Patrolling CD8+ T lymphocytes detect tainted cells by scanning the peptide–MHC-I (pMHC-I) complexes via T cell receptors and induce their apoptosis. Triaging the vast pool of cytosolic degradation products to find the few peptides that have a high affinity for MHC-I requires a sophisticated machinery, the peptide-loading complex (PLC). 





Structural overview of the MHC-I PLC. 
The PLC can be divided into three parts, ER-luminal, TM, and cytosolic. The ER-luminal part consists of two editing modules, M1 and M2, each of which contains one Tsn, ERp57, Crt, and MHC-I. MHC-I proteins are heterodimers formed of a variable α heavy chain (αHC) and an invariant, light β2 microglobulin (β2m). αHC comprises three soluble domains, two of which, α1 and α2, form the peptide-binding groove (PBG). MHC-Is have an N-linked branched glycan that reflects their loading status: A terminal glucose allows recognition and binding by Crt and acts as a signal that MHC-I should be recruited to the PLC for peptide editing; antigen-loaded MHC-Is that exit the ER are deglucosylated. Newly synthesized “empty” MHC-I proteins (eMHC-I) are unstable; in the PLC, Tsn acts as an MHC-I chaperone. Tsn is the central component of the editing modules. It has two ER-luminal domains: N-terminal TN and C-terminal TC. M1 and M2 are organized around a pseudosymmetry axis at the interface between the two Tsns. Tsn forms a complex with MHC-I and accelerates the off-rate of low-affinity MHC-I–bound peptides to perform peptide editing. Tsn is also disulfide-bonded to ERp57, a four-domain protein playing a structural role. Crt consists of three soluble domains, a globular lectin domain with a binding site for the monoglucosylated branch of the N-linked MHC-I glycan, a flexible P domain that extends over the PBG and contacts ERp57, and a calcium-sensing C domain with an extended α-helix that contacts Tsn. The transporter associated with antigen processing (TAP) is the main component of both the TM and cytosolic parts of the PLC. TAP shuttles peptides from the cytosol to the ER, providing the PLC with its substrate for antigen processing. TAP is a heterodimer of TAP-1 and TAP-2, each of which has an N-terminal four-helix TM domain, TMD0, that provides a docking site for the TM helix of Tsn. A TM helix also anchors MHC-I to the ER membrane.

Anchored to the endoplasmic reticulum (ER) membrane, this large macromolecular assembly integrates several MHC-I antigen-processing functions into a single molecular machine: antigen transport to the ER, MHC-I stabilization during the loading process, and catalytic selection of high-affinity antigenic peptides (or peptide editing). 

Many dynamic events take place in the complex, such as assembly, the roles of the various components in the formation of a stable complex, the recruitment of suboptimally loaded MHC-I, the process of peptide selection, and the release of antigen-loaded MHC-I. 

They can be hindered by immune evasion mechanisms, rendering the PLC inoperative. Here, we present the structure and conformational dynamics of the PLC at the atomic level. We integrated the cryo-EM density of the complex with high-resolution structural information on individual PLC components to obtain an atomistic model.


Atomistic model of the MHC-I peptide-loading complex. 
(A) The 1.6-million-atom molecular dynamics simulation system contains the complete human MHC-I PLC (75.939 atoms), embedded in a POPC lipid bilayer (101.036 atoms) and solvated by explicit water with Na+ and Cl− ions. (Only a small slab of water is shown for clarity.) 
(B) The PLC model was built by fitting atomistic subunit structures to the cryo-EM density for a single editing module (EMD-3906) and then duplicating this module and fitting to the cryo-EM data (EMD-3094) for the pseudosymmetric assembly (cryo-EM density for a single module shown as a surface).

This atomic structure was embedded into a solvated lipid bilayer and subjected to all-atom molecular dynamics (MD) simulations, in which the motions of the complex unfold on the microsecond time scale. We also simulated alternative models of the PLC where individual domains, subunits, or even large parts of the complex were removed and compared protein dynamics in these truncated systems to what we observed in the full complex. This computational structural biology approach pinpoints the origin of dynamic events and relates them to biological functions.  

We have shown that the stability of the human MHC-I PLC requires two editing modules. A single-module PLC cannot assemble the circular belt formed by ERp57 and Crt that encloses the central scaffold formed by the two Tsn•MHC-I dimers. Our results also highlight the crucial role of Tsn in bridging PLC components together. We found five protein–protein interfaces involving Tsn, both intra- and intermodule. Sampling of myriads of different peptide/MHC-I allomorphs requires a precisely coordinated quality control network in a single macromolecular assembly, including the transporter associated with antigen processing TAP1/2, the MHC-I heterodimer, the oxidoreductase ERp57, and the ER chaperones tapasin and calreticulin. Proofreading by MHC-I editing complexes guarantees that only very stable peptide/MHC-I complexes are released to the cell surface.

My comment: The authors mention the REQUIREMENT  for the stability of the human MHC-I PLC machine of two editing modules, since just one cannot assemble the circular belt, and furthermore, antigen processing TAP1/2, the MHC-I heterodimer, the oxidoreductase ERp57, and the ER chaperones tapasin and calreticulin associated with transport.   This indicates that this sophisticated macromolecular nanomachine is irreducibly complex. 

Interfaces between ER-luminal Tsn domains and other PLC components. TM regions are not shown. 

This complex environment modulates MHC-I dynamics, resulting in a tighter binding groove that is stabilized in a peptide receptive conformation.

1. https://phys.org/news/2020-08-giant-nanomachine-aids-immune.html?fbclid=IwAR2JepKjofCYjTYA_x1uBoz8yqGW81rP6Vh6s7iPL1yg5ishSq3S47Ew3bo
2. https://sci-hub.tw/https://www.pnas.org/content/117/34/20597
3. https://cordis.europa.eu/project/id/789121
4. https://sci-hub.tw/https://pubmed.ncbi.nlm.nih.gov/29606337/

The human immune system is irreducible, depending on several macromolecular complexes that work in a joint venture

https://reasonandscience.catsboard.com/t1289-molecular-machines-in-biology#7928

1. Waste management (or waste disposal) includes the activities and actions required to manage waste from its inception to its final disposal. This includes the collection, transport, treatment, and disposal of waste, together with monitoring and regulation of the waste management process, and is always preceded by careful planning and foresight of the entire process by waste management engineers,  and implemented virtually simultaneously. 

2. Biological cells have cleverly engineered mechanisms that grind molecular protein garbage ( Proteasome Garbage Grinders ), coordinate loading and translocation of the waste products ( by superb Multisubunit peptide-loading complexes (PLC) ) to the waste disposal site, where the waste products are processed and sorted out (Histocompatibility complex class I (MHC-I) with 1,6 million atoms that to work with atomic precision ), and the final products are transported to the surface of the cell through the exquisite secretory pathway. There, T-Cells scan the MHC-I with receptors, and recognize when the cell was infected by foreign invaders, and induce their apoptosis ( cell suicide)
At least 9 macromolecular complexes need to work together in a joint venture, which communicate with each other to orchestrate this masterfully information-based process through signaling languages. If one of the complexes in the pathway is missing, no deal, the immune system cannot do its job, and the organism cannot survive, and dies. Of course, all this incredible marvel of molecular engineering had to be born fully set up. No stepwise evolutionary process would lead to such a system. 

3. Therefore, the intelligent design theorist is justified to posit an unfathomably clever intelligent designer with foresight, who knew how to implement such a masterfully crafted waste management system on a molecular scale.    



The immune system is the body’s natural defense against infection and disease, including cancer, and protects the body from substances that can cause harm, such as bacteria and viruses (also called germs).
The cells of the immune system continuously flow through the body, looking for germs that may be invading the body. The immune system recognizes invaders by their antigens, which are proteins on the surface of the invading cells . Every cell or substance has its own specific antigens, and a person’s cells carry “self-antigens” that are unique to that individual.

People carry self-antigens on normal cells, such as liver, colon, and thyroid cells. Cells with self-antigens are typically not a threat. Invading germs, however, do not originate in the body and so do not carry self-antigens; instead, they carry what are called “nonself-antigens.”

The immune system is designed to identify cells with nonself-antigens as harmful and respond appropriately. Most immune cells release cytokines (messengers) to help them communicate with other immune cells and control the response to any threats. When, for example,   the immune system’s first barrier, the skin, is broken, harmful substances can easily enter the body.  As soon as the injury occurs, immune cells in the injured tissue begin to respond and also call other immune cells that have been circulating in your body to gather at the site and release cytokines to call other immune cells to help defend the body against invasion. The immune cells can recognize any bacteria or foreign substances as invaders. Immune cells, known as natural killer cells, (Natural Killer (NK) Cells are lymphocytes in the same family as T and B cells) begin to destroy the invaders with a general attack. Now, we will give a closer look at how that happens. 4

Our body constantly encounters pathogens or malignant transformation. Cells that are infected by a virus or carry a carcinogenic mutation produce proteins foreign to the body. The adaptive immune system fights back unwanted invaders through highly sophisticated defense mechanisms.  One of the central hinges of human adaptive immunity is the major histocompatibility complex (MHC) class I antigen presentation pathway. 

Antigenic peptides result from the degradation of unwanted exogenous proteins  ( proteasomal degradation products ) inside the cell. They are generated in the cytosol by proteasomal protein degradation. These antigens are, of the most part, short peptides (8 to 12 amino acids) resulting from the degradation of intracellular proteins.  

Triaging the vast pool of cytosolic degradation products to find the few peptides indicating infection or antigenic invasion requires sophisticated machinery, the highly dynamic multisubunit peptide-loading complex (PLC). The products for degradation are edited by PLC. 

PLC contains as key constituents a transporter associated with antigen processing (TAP) and the MHC I-specific chaperone tapasin (Tsn). 

The antigenic invaders are loaded, and  TAP transports the proteasomal degradation (antigen) products from the cytosol intracellularly to the endoplasmic reticulum ER, where they are loaded and proofread by major histocompatibility complex class I proteins (MHC-I), which play a pivotal role, they are a cornerstone of the human adaptive immune system.5, being responsible for processing antigens that allow killer T cells to distinguish between healthy and compromised cells. Proofreading by MHC-I editing complexes guarantees that only very stable peptide/MHC-I complexes are released to the cell surface.

The peptide-MHC-I complexes then move via a secretory pathway to the cell surface, presenting their antigenic load to cytotoxic T-cells.

Peptides exposed at the cell surface, therefore, mirror cellular contents: In healthy cells, only peptides from the “self” are exposed; in cells compromised by a virus or cancer-causing mutation, both self and “nonself” peptides, either viral or mutated, are exposed and displayed. A sampling of myriads of different peptide/MHC-I allomorphs ( different protein forms) requires a precisely coordinated quality control network in a single macromolecular assembly, including the transporter associated with antigen processing TAP1/2, the MHC-I heterodimer, the oxidoreductase ERp57, and the ER chaperones tapasin and calreticulin.  3 The stability of the human MHC-I PLC requires two editing modules. A single-module PLC cannot assemble the circular belt formed. There is also a crucial role of Tsn in bridging PLC components together.

Patrolling  T lymphocytes ( T cells ) detect and identify tainted cells by scanning the peptide MHC  complexes via T cell receptors and induce their apoptosis ( cell suicide).  This is how our immune system defends us against pathogens. 

Consider what is required for this pathway to be able to operate: 

-  Proteasome Garbage Grinders 6 are analogous to shredders or garbage disposals, indispensable to destroy cellular components, breaking them down to their constituent parts, which can then be recycled
-  Multisubunit peptide-loading complex (PLC)  is essential for establishing a hierarchical immune response. 7
-  a transporter associated with antigen processing (TAP1/2) is essential for peptide presentation to the major histocompatibility complex (MHC) class I molecules on the cell surface and necessary for T-cell recognition 8
-  MHC I-specific chaperone tapasin (Tsn) is essential for the assembly of the PLC and for efficient MHC I antigen presentation. 9
-  Oxidoreductase ERp57 is essential through the participation in the assembly of the major histocompatibility complex class 1. 10
-  ER chaperones tapasin: Tapasin is an essential adapter protein recruiting MHC I molecules to TAP, catalyzes peptide loading of MHC I. 11
-  Histocompatibility complex class I (MHC-I) is extremely important and essential for the adaptive immune system. 12, 15
-  The secretory pathway is ubiquitous to all cells and essential for the export of proteins.13
-  Cytotoxic T-cells are essential in host defense against pathogens that live in the cytosol, the commonest of which are viruses. These cytotoxic T cells can kill any cell harboring such pathogens by recognizing foreign peptides. 14



1. https://phys.org/news/2020-08-giant-nanomachine-aids-immune.html?fbclid=IwAR2JepKjofCYjTYA_x1uBoz8yqGW81rP6Vh6s7iPL1yg5ishSq3S47Ew3bo
2. https://sci-hub.tw/https://www.pnas.org/content/117/34/20597
3. https://cordis.europa.eu/project/id/789121
4. https://www.sitcancer.org/connectedold/p/patient/resources/melanoma-guide/immune-system
5. https://www.frontiersin.org/articles/10.3389/fimmu.2017.00292/full
6. https://reasonandscience.catsboard.com/t1851-proteasome-garbage-grinders
7. https://pubmed.ncbi.nlm.nih.gov/29107940/
8. https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/transporter-associated-with-antigen-processing
9. https://www.nature.com/articles/srep17341
10. https://link.springer.com/article/10.2478/s11658-011-0022-z
11. https://faseb.onlinelibrary.wiley.com/doi/full/10.1096/fj.12-217489
12. https://en.wikipedia.org/wiki/Major_histocompatibility_complex
13. https://jlb.onlinelibrary.wiley.com/doi/pdf/10.1189/jlb.1208774
14. https://www.ncbi.nlm.nih.gov/books/NBK27101/#:~:text=Armed%20effector%20cytotoxic%20CD8%20T,to%20MHC%20class%20I%20molecules.
15. https://onlinelibrary.wiley.com/doi/full/10.1002/ece3.5373

The peptide-loading complex (PLC) is a biological nanomachine with 1,6 million atoms that has to work with atomic precision in order to efficiently protect us against pathogens that cause disease. All atoms are exactly located in the precise place to do their job; identifying "foreign" protein fragments and setting them up for t-cells to eliminate, exists in every cell of our body. 

Take just a moment to ponder the immensity of this enzyme. The entire complex is composed of over 1,6 million atoms, each of which plays a vital role. The handful of atoms that actually perform the chemical reaction are the central players. But they are not the only important atoms within the enzyme--every atom plays a supporting pan. The atoms lining the surfaces between subunits are chosen to complement one another exactly, to orchestrate the shifting regulatory motions.

1. Cells are literally chemical nano-factories, that operate based on molecular machines, protein robots, kinesin protein carriers, autonomous self-regulated production lines, generate energy through turbines, have neuron transistors, and computers
2. Such things are always set up by intelligent designers
3. Therefore, most probably, Cell factories are the product of an intelligent designer.

https://reasonandscience.catsboard.com/t2809-analogy-viewed-from-science#7675

Molecular machines
https://reasonandscience.catsboard.com/t1289-molecular-machines-in-biology

https://en.wikipedia.org/wiki/Molecular_machine

Science papers:
1.“Biological machines: from mills to molecules,” Nature Reviews Molecular Cell Biology, Vol. 1:149-153 (November, 2000).
2.Thomas Köcher & Giulio Superti-Furga, "Mass spectrometry-based functional proteomics: from molecular machines to protein networks," Nature Methods (October, 2007).
3."Crystalline Molecular Machines: A Quest Toward Solid-State Dynamics and Function," Accounts of Chemical Research, Vol. 39(6):413-422 (2006).
4."Molecular Machines," Annual Review of Biomedical Engineering, Vol. 6:363-395 (2004).
5."The Closest Look Ever At The Cell's Machines,” ScienceDaily.com (January 24, 2006).
6."The Cell as a Collection of Protein Machines: Preparing the Next Generation of Molecular Biologists," Cell, Vol. 92:291 (February 6, 1998).
7.Walter Neupert, "Highlight: Molecular Machines," Biological Chemistry, Vol. 386:711(August, 2005).
8.Seiji Kojima and David F. Blair, “The Bacterial Flagellar Motor: Structure and Function of a Complex Molecular Machine,” International Review of Cytology, Vol. 233:93-134 (2004).
9.Hugo ten Cate, “The blood coagulation system as a molecular machine,” BioEssays, Vol. 25:1220-1228 (2003).
10.John L Woolford, Jr, “Assembly of ribosomes and spliceosomes: complex ribonucleoprotein machines,” Current Opinion in Cell Biology, Vol. 21(1):109-118 (February, 2009).

Proteins are robots
Nature's robots: A history of proteins: Tanford, C., Reynolds, J
Shape-shifting molecular robots respond to DNA signals
When Nature's Robots Go Rogue: Exploring Protein ...
- Document - Nature's Robots: a History of Proteins - Gale
Bio-Inspired Self-Organizing Robotic Systems
GACR - Proteins - Multi-robot Systems
Buy Nature's Robots: A History of Proteins Book Online at Low ...

Molecular production lines
A molecular production line | Nature Chemistry
molecular assembly line | News and features
The molecular biology of production cell lines. - NCBI
Cell-Like 'Molecular Assembly Lines' of ... - Cordis
Biologically inspired molecular assembly lines - MIT Media Lab
DNA-based assembly lines and nanofactories

Cell factories
https://reasonandscience.catsboard.com/t2245-abiogenesis-the-factory-maker-argument

Microbial cell factory is an approach to bioengineering  which considers microbial  cells as a production facility in which the optimization process largely depends on metabolic engineering
https://en.wikipedia.org/wiki/Microbial_cell_factory

Science papers:
The Molecular Fabric of Cells  BIOTOL, B.C. Currell and R C.E Dam-Mieras (Auth.)
Plant Cells as Chemical Factories: Control and Recovery of Valuable Products
Fine Tuning our Cellular Factories: Sirtuins in Mitochondrial Biology
Cells As Molecular Factories
Eukaryotic cells are molecular factories in two senses: cells produce molecules and cells are made up of molecules.
Ribosome: Lessons of a molecular factory construction
Nucleolus: the ribosome factory
Ribosome: The cell city's factories
The Cell's Protein Factory in Action
What looks like a jumble of rubber bands and twisty ties is the ribosome, the cellular protein factory.
Chloroplasts are the microscopic factories on which all life on Earth is based.
Visualization of the active expression site locus by tagging with green fluorescent protein shows that it is specifically located at this unique pol I transcriptional factory.

The brain is a " Uber-Computer "
https://reasonandscience.catsboard.com/t2734-the-brain-is-a-uber-computer-far-more-sophisticated-that-man-made-computers

The Cell is a super computer
https://reasonandscience.catsboard.com/t2712-the-cell-is-a-super-computer?highlight=computer

Your Cortex Contains 17 Billion Computers
Yes, the brain is a computer…
An 83,000-Processor Supercomputer Can Only Match 1% of Your Brain
Why cells are like computers—And how ‘hacking’ them could lead to new diagnostic tools
Hidden Computational Power Found in the Arms of Neurons
Dendritic action potentials and computation in human layer 2/3 cortical neurons
Single neuron dynamics and computation
What can a single neuron compute?
Brain-Inspired Computing Could Lead to Better Neuroscience

Neurons are transistors
Synaptic transistor
https://en.wikipedia.org/wiki/Synaptic_transistor

Neuron transistor behaves like a brain neuron - Phys.org
Digital: From Neurons to Transistors - LinkedIn
Capacitive neural network with neuro-transistors | Nature
A neuron-astrocyte transistor-like model for neuromorphic dressed neurons.
Electrolyte-gated organic synapse transistor interfaced ... - arXiv

Is the cell really a machine? A response

https://reasonandscience.catsboard.com/t1289-molecular-machines-in-biology#8221

https://sci-hub.ren/https://www.sciencedirect.com/science/article/abs/pii/S0022519319302292?via%3Dihub

Claim: The machine conception of the cell (MCC) fails to make an appropriate sense of cellular phenomena for two basic reasons. The first has to do with the fact that cells, unlike machines, are self-organizing, fluid systems that maintain themselves in a steady state far from thermodynamic equilibrium by continuously exchanging energy and matter with their surroundings. 2
Response: The basic structure of modern cells has largely been driven by “alimentary efficiency,” or the input-output efficiency of turning available nutrients into energy and basic building blocks. In
dynamic environments, the ability of the cell to react quickly, and decisively is vital to ensure survival and reproduction. An important type of response, indeed, is the cell’s biosynthetic response, i.e., the response of its production systems 1.  So rather than denying through this fact that cells operate machine-like, it reinforces the observation.  The cell has had fully developed and with competencies that allow for efficiency through energy and building block conservation while maximizing responsiveness to environmental changes.

Recycled aluminum is less expensive to produce than the primary material because it takes 90% less energy to process.

In the same sense, as in a factory, full of machines, recycling helps save and economize energy, the cell’s production system obtains part of its efficiency from closed cycles both within the cell and within the ecosystem of which it is part. The cell recycles building blocks such as nucleotides and amino acids. This saves energy and time for the resynthesis of amino acids, facilitated by the limited number of building blocks and the commonality of biomolecules.

Claim: by virtue of their microscopic size, cells (and their molecular constituents, even more so) are subject to very different physical conditions compared to macroscopic objects, like machines. 
Response:  This is not a valid objection. The size or forces employed do not change the fact that proteins are molecular machines in a literal sense.

It is now clear that most functions in the cell are not carried out by single protein enzymes, colliding randomly within the cellular jungle, but by macromolecular complexes containing multiple subunits with specific functions (Alberts 1998 ). Many of these complexes are described as “molecular machines.” 3

Claim: These results are bringing about a radical shift in how we think about the cell, replacing a mechanical, neatly ordered, rigid picture with one that is inherently stochastic, more plastic, and less predictable.
Response: This is not an accurate description of what recent advances in scientific investigations have brought to light. The processes are NOT inherently stochastic, but rather the opposite is the case.
The mechanisms are far more varied, ingeniously complex, interlinked, and interdependent than it was ever devised or predicted. The more science advances and investigates, the more, new layers of complexity come to light.

Claim: The traditional view of the mitotic spindle apparatus as a molecular machine that is built through a defined irreversible set of instructions is gradually being replaced. It can instead be envisaged as a self-regulating dynamic structure where multiple pathways of MT [microtubule] generation are spatially and temporally controlled and integrated, constantly ‘talking’ to one another and modifying the behavior of their MTs in order to
maintain a flexible yet robust steady-state spindle. ( Duncan and Wakefield, 2011 , p. 330)
Response:  The mitotic spindle is a molecular machine capable of distributing the genome to the daughter cells with stunning precision. 4 At the cellular level, the mitotic spindle apparatus is arguably the most complicated piece of machinery in existence. Its basic function is to isolate and separate the chromosomes during cell division. 5 Nothing of the new findings changes that fact. 

Claim: when we have started using techniques that allow us to examine the cellular architecture in real-time, we have found that many of the cell’s compartments and organelles are not fixed machineries at all, but stable macromolecular fluxes.
Response:  I don't know why the author writes about " fixed machineries ". Nobody claims that machines are static, fixed, but always dynamic, performing specific tasks. Wikipedia describes a machine as a mechanical structure that uses power to apply forces and control movement to perform an intended action. What we observe, IMHO, the more capable we are to investigate cellular behavior, how precise, controlled, often close to the physically possible cells perform their actions, in some cases even using quantum mechanics. I would describe Cells rather as an entire park of interconnected factories, containing a multitude of machines and machine production lines. 

Claim: The potentially innumerable ways in which proteins can come together to form functional aggregates, the extraordinarily wide range of factors that can change their conformational state, and the dynamic and ephemeral nature of these associations has led some researchers to argue that many of the protein complexes found in the cell are better understood as pleomorphic ensembles than as molecular machines
Response:  We use the term pleomorphic ensembles (PEs) to describe these clusters because they have dynamic compositions and sizes and have rapid turnover of their molecular constituents; this plasticity can be highly responsive to cellular signals. 6  Rather than replacing the machine analogy, i would add this feature as an advancement of how molecular machines perform and behave. 

We can conceive that the cell may be a billion, or even a trillion times more complex than anyone has understood. 7  

As Mayer et al. put it, after considering the vast range of potential configurations that a single transmembrane receptor complex for platelet-derived growth factor (PDGF) can adopt, the activated receptor looks less like a machine and more like a pleiomorphic ensemble or probability cloud of an almost infinite number of possible states, each of which may differ in its biological activity. ( Mayer, 2009 , p. 81.2)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2776906/

Rather than removing the design argument, this description does solidify it. This adds a huge amount of sophistication to how molecules employed in cells behave, which is better explained by design, rather than not.


Protein function relies on "flexible joints." This study, published in Proceedings of the National Academy of Sciences (PNAS), examines the link between function and flexibility by modelling proteins like elastic networks. In this model, proteins are made of flexible (polar) and rigid (hydrophobic) amino acids connected by molecular "springs". If some regions of the protein are flexible enough, they form a "floppy" channel, and the entire molecular machine can bend like a hinge. This motion allows them to bind effectively to other molecules. The binding between a ligand and a stiff or flexible protein can be thought as a ball landing on a rock or a soft pillow. The ball is likely to bounce away after hitting the rock, but the pillow is more likely to accept it. Therefore, the flexible protein is a better binder.
https://www.eurekalert.org/pub_releases/2018-05/ifbs-htc052918.php




1. https://ink.library.smu.edu.sg/cgi/viewcontent.cgi?article=2060&context=lkcsb_research
2. https://www.sciencedirect.com/science/article/abs/pii/S0022519319302292?via%3Dihub
3. http://jcb.rupress.org/content/152/1/F1.full
4. https://sci-hub.st/https://science.sciencemag.org/content/294/5542/543
5. https://phys.org/news/2013-10-machinery-mitosis-kinetechores-centrioles-chromosome.html
6. https://pubmed.ncbi.nlm.nih.gov/24314076/#:~:text=We%20use%20the%20term%20pleomorphic,highly%20responsive%20to%20cellular%20signals.
7. https://reasonandscience.catsboard.com/t3057-intelligent-cells-a-trillion-times-more-complex-than-anyone-has-understood-by-evolution-or-design#8118

Proteins Often Form Large Complexes That Function as Machines

As proteins progress from being small, with a single domain, to being larger with multiple domains, the functions they can perform become more elaborate. The most complex tasks are carried out by large protein assemblies formed from many protein molecules. Now that it is possible to reconstruct biological processes in cell-free systems in a test tube, it is clear that each central process in a cell—including DNA replication, gene transcription, protein synthesis, vesicle budding, and transmembrane signaling—is catalyzed by a highly coordinated, linked set of many proteins. For most such protein machines, the hydrolysis of bound nucleoside triphosphates (ATP or GTP) drives an ordered series of conformational changes in some of the individual protein subunits, enabling the ensemble of proteins to move coordinately.


“Protein machines” can carry out complex functions.
These machines are made of individual proteins that collaborate to perform a specific task. The movement of proteins is often coordinated and made unidirectional by the hydrolysis of a bound nucleotide such as ATP. Conformational changes of this type are especially useful to the cell if they occur in a large protein assembly in which the activities of several different protein molecules can be coordinated by the movements within the complex, as schematically illustrated here.

In these machine-like complexes, the appropriate enzymes can be positioned to carry out successive reactions in a series—as during the synthesis of proteins on a ribosome, for example. And during cell division, a large protein machine moves rapidly along DNA to replicate the DNA double helix

Proteins are robots

JA Reisz: When nature's robots go rogue: exploring protein homeostasis dysfunction and the implications for understanding human aging disease pathologies 2018 Apr. 15
https://pubmed.ncbi.nlm.nih.gov/29540077/

Yuan F. Zheng: ( Some ) Proteins behave like mobile robots and take adequate paths to form a robotic team (crystal). 3/5/2007
https://www2.ece.ohio-state.edu/~zheng/publications/Mobile-protein.pdf

Do you believe that the making and assembly of a machine is better explained by coincidence or intelligence?

A machine is made of different parts that interact together, to convey a specific function and using energy.

We create two hypotheses and predictions.
The first is that coincidence or random chance is able to create computers with Hardware and software, using codes and languages, instantiating information, and after encoding, information transfer, translation, and decoding that instructional information is used to construct factories full of machines, production lines, driven by energy made by energy turbines.
And the other hypothesis is that intelligence is capable to instantiate all these things.
Based on our background knowledge and experience, which of the two hypotheses and predictions do you think will be successful and meet the prediction?


The blood coagulation system:  “is a typical example of a molecular machine, where the assembly of substrates, enzymes, protein cofactors etc.accelerate the rate of coagulation.”
Ribosome:  is an “RNA machine” that “involves more than 300 proteins and RNAs” to form a complex where messenger RNA is translated into protein.
Bacteriorhdopsin:  “is a compact molecular machine” that uses sunlight energy to pump protons across a membrane.
Myosin:  is a molecular motor that moves along a “track” to form the basis of muscle movement or to transport cargoes within the cell.
kinesin is a protein machine that binds to and carries cargoes by “crawls hand-over-hand along a microtubule” in the cell.
Tim/Tom Systems are selective protein pump machines that import proteins across the inner (Tim) and outer (Tom) membranes of mitochondria into the interior matrix of the mitochondria.
The calcium pump is an “amazing machine with several moving parts“ that transfers calcium ions across the cell membrane.
Cytochrome C Oxidase: Cytochrome C Oxidase qualifies as a molecular machine “since part of the redox free energy is transduced into a proton electrochemical gradient.”
Proteosome is a large molecular machine whose parts must be must be carefully assembled in a particular order.
Cohesin is molecular machine “multisubunit protein complex"52 and “a macromolecular complex that links sister chromatids together at the metaphase plate during mitosis.”
Condensin is a molecular machine that helps to condense and package chromosomes for cell replication. It is a five subunit complex, and is “the key molecular machine of chromosome condensation.”
ClpX is a molecular machine that uses ATP to both unfold proteins and then transport unfolded proteins into another complex in the cell. It moves these proteins into the ClpP complex.
Immunological Synapse  is a molecular machine that serves as an interface to activate of T cells.
Glideosome is a “macromolecular complex” and an “elaborate machine”57 whose function is to allow protozoa to rely on gliding motility over various substrates.
Kex2 is a molecular machine that facilitates cell fusion during the mating of yeast; it likely works by degrading cell walls.
Hsp70 is one of many molecular machines that serve as chaperones that not only assist other proteins in reaching a proper functional conformation (i.e. proper folding)
Hsp60 is another chaperone machine – it is tailored to provide “an enclosed environment for folding proteins which totally protects them as they fold.”
Protein Kinase C is a molecular machine that is activated by certain calcium and diacylglycerol signals in the cell.
SecYEG PreProtein Translocation Channel is vital to the operation of “translocation machinery” which works to move molecules across membranes in the cell.
Hemoglobin is a remarkable molecular machine that uses motion and small structural changes to regulate its action.”
T4 DNA Packaging Motor is one of various packaging motors that are “powerful molecular motors” which emplace viral genomes into capsules called procapsids.
Smc5/Smc6 is a complex machine that is involved with the structural maintenance of chromosomes with regards to cohesions and condensins
Cytplasmic Dynein is a machine involved with cargo transport and movement cell that functions like a motor with a “power stroke.”
Mitotic Spindle Machine is a highly dynamic self-assembling complex molecular machine composed of tubulin, motors, and other molecules
DNA Polymerase is a multiprotein machine that creates a complementary strand of DNA from a template strand.
The kinetochore is a “proteinaceous structure that assembles on centromeric chromatin and connects the centromere to spindle microtubules.”
MRX Complex forms telomere length counting machinery that measures the integrity of telomeres, the structures that protect the ends of eukaryotic chromosomes.
Apoptosome / Caspase: While many molecular machines keep a cell alive, there are even machines that are programmed to cause cell death, or apoptosis.
Type III Secretory System: This machine, often called the T3SS, is a toxin injection machine used by predatory bacteria to deliver deadly toxins into other cells.
Type II Secretion Apparatus: The T2SS is a complex nanomachine that translocates proteins across the outer membrane of a bacterium.89
Helicase/Topoisomerase Machine work together to properly unwrap or unzip DNA prior to transcription of DNA into mRNA or DNA replication.
RNA degradasome “multiprotein complex involved in the degradation of mRNA” or trimming RNAs into their active forms in E. coli bacteria.
Photosynthetic system: The processes that plants use to convert light into chemical energy a type of molecular machines.e amount of light aborbed.

Julie A. Reisz et.al., (2019): Proteins have been historically regarded as “nature’s robots”: Molecular machines that are essential to cellular/extracellular physical-mechanical properties and catalyze key reactions for cell/system viability. However, these robots are kept in check by other protein-based machinery to preserve proteome integrity and stability. During aging, protein homeostasis is challenged by oxidation, decreased synthesis, and increasingly inefficient mechanisms responsible for repairing or degrading damaged proteins. In addition, disruptions to protein homeostasis are hallmarks of many neurodegenerative diseases and diseases disproportionately affecting the elderly.

Protein homeostasis networks are regulated by cell stress signaling pathways that respond to events such as unfolded/misfolded proteins in the endoplasmic reticulum or accumulation of toxic protein aggregates. Dysfunction of these quality control mechanisms and resultant intracellular accumulation of abnormal proteins in the forms of protein inclusions and aggregates occur in almost all tissues of an aged organism. Age is indeed the strongest risk factor for many diseases including neurodegenerative disorders, coronary heart disease, and cancer. Aging is a complex, multifactorial process characterized by a progressive decline in physiological functions at multiple levels. Maintenance of the aging transcriptome, proteome, and metabolome is essential to preserve cell functionality and the ability to respond and adapt to tissue-specific chronic and acute stressors. In mammals, hallmarks of aging tissues include declining rates of self-renewal capability (e.g., protein homeostasis dysfunction, stem cell exhaustion), accumulation of damage to DNA (e.g., epigenetic alterations) and proteins (e.g. carbonylation), genomic instability, impaired mitochondrial metabolism, and increased levels of reactive oxygen species and reactive nitrogen species (ROS and RNS, respectively), among other traits. Exploration of these attributes in mice has identified relationships among senescence, transcriptional regulation, increased mutational burden, and maintenance of proteome integrity – processes normally regulated by a dedicated set of molecular machinery that collectively maintain protein homeostasis, also termed proteostasis. Disrupted proteostasis also underlies many neurodegenerative diseases and cancers, illustrating the complex interplay between aging and pathology. The biological mechanisms and function of each aspect of the proteostasis machinery are areas of high importance in cell and tissue physiology. 


Overview of protein quality control machinery.
To preserve proteome integrity, cells contain a diverse set of proteins that work together to ensure proper structure and localization of nascent and existing proteins. Figure adapted from Henning and Brundel

Cellular proteome imbalance results through numerous mechanisms in aging
Mitochondria and oxidative stress
Aging cells are widely known to possess less functional mitochondria and higher basal levels of reactive oxygen species (ROS) than their younger counterparts, two closely related attributes. Exposure to ROS results from exogenous sources such as radiation (e.g., gamma rays in therapy, sunlight), smoking, and other environmental sources, accumulating in cells over time. Importantly, there are numerous endogenous routes of ROS generation, including uncoupling of the electron transport chain (ETC) (i.e., reaction of leaked electrons with O2 to produce superoxide) and by the activity of the NADPH oxidases. Once formed, these species react very rapidly with each other and/or nearby biomolecules, often culminating in irreversible damage to DNA, proteins, and lipids. Cells are armed with efficient small molecule (e.g., glutathione, ascorbate) and enzymatic (e.g., peroxiredoxins, glutathione peroxidase, catalase, superoxide dismutase) tools to counteract ROS/RNS formation, but these systems can become overwhelmed and/or incapacitated with acute or chronic high levels of oxidants. 1

Comment: Preventing the increased levels of reactive oxygen species and reactive nitrogen species (ROS and RNS, respectively) is life-essential, and is a problem that even the first cells had to be able to cope with. 

Jie Xu (2013): Geochemical environments for occurrence of mineral surface-associated radicals Mineral surfaces can induce the formation of radical species involving reactions with H2O, O2, NOx, CO2, and SO2, etc., in atmospheric, aqueous and solid rock or soil environments when exposed to ultraviolet radiation, impact shocks, or mechanical grinding. The radicals formed are highly reactive and capable of oxidizing organic molecules in close proximity. For example, hydroxyl radical (OHd ) – the most studied radical species because of its prevalence in biological and environmental systems – reacts rapidly with carbohydrates, fatty acids, RNA, DNA, nucleic acids and other biological molecules, leading to alteration or decomposition of these molecules. Reactive oxygen species (ROS) associated with mineral surfaces are well documented in biomedical studies. On the molecular level, silica, pyrite, and iron oxides can cause severe damage of RNA and nucleic acids in vitro, and peroxidize phospholipids both in vitro and in vivo. UV-illuminated titanium oxides exhibit bactericidal effect toward Escherichia coli and Pseudomonas aeruginosa cells by breaking down the cell walls also via surface-bound OHd. In general, the ability of minerals to produce ROS represents their potential to degrade biomolecules by oxidation, which may have had a direct or indirect impact on early life by affecting the organic inventory available for prebiotic synthesis and/or by affecting the stability of ‘‘protocell’’ amphiphilic membranes in contact with these mineral surfaces. Thus, ROS, in addition to other mineral properties such as hydrophilicity, hydrophobicity, surface-charge, and Hamaker constants, etc. may have influenced evolution of life on Earth and other solid terrestrial worlds. Beyond the oxides and asbestiform minerals, reactive radicals and intermediates including superoxide, peroxide, hydroxyl, and carbonyl have recently been identified in a wide range of minerals present in simulated or natural geochemical settings. The role of mineral aerosol surfaces in catalyzing redox reactions of absorbed gaseous species in the Earth’s atmosphere is also being recognized. Based on samples from East Asia and the Sahara Desert, these aerosols usually consist of insoluble cores of silica and alumina, with soluble solid shells of carbonate and trace metals, where the metals are the centers for ROS generation. The presence of dense mineral aerosols and sand dusts can influence tropospheric chemistry in terms of the types and concentrations of reactive (radical) species, and the total redox capacity. These kinds of aerosols may affect the stability of organic molecules, if present, in other planetary atmospheres.

ROS oxidizes and destroys amino acids and proteins. Whether ROS promote synthesis or degradation depends on the reaction conditions, including the compounds present and their concentrations, the solution pH, ionic strength, temperature pressure, illumination, etc. Another class of molecules found in meteorites are long-chain monocarboxylic acids. These molecules are amphiphiles and self-assemble into bilamellar vesicles similar to the phospholipid bilayers comprising all extant cell membranes. The oxidation and destruction of membranes is a well-established reaction called membranolysis. Thus, ROS could have affected the stability of the membranes of protocells and the earliest cells on Earth. A final example here is provided by the pyrimidines and purines found in meteorites, which would have been the building blocks for pre-RNA, RNA and DNA molecules. RNA is known to be highly susceptible to degradation under a variety of conditions and DNA is more stable, but both are degraded by ROS in solution and by mineral surface-associated ROS. We have studied reactive oxygen species, but free radicals and other reactive species may also have been formed on mineral surfaces in reactions involving other gases, such as CO2, N2, SO2, and NH3, etc., which would have been present on early Earth. The high rate of bolide impacts on early Earth could also have generated radicals, such as silyly (Sid ) and siloxy (SiOd ), on silicate minerals by homolytic cleavage of Si–O–Si bonds. Furthermore, we note that in addition to the potential effect of mineral surface-generated free radicals on pre-biotic organic inventory and primitive cell membrane viability, mineral surfaces could also have influenced several other types of prebiotic reactions. Conclusions In summary, oxide minerals of similar particle sizes and surface areas show different ROS-forming abilities, and two major pathways of OHd and H2O2 formation are identified. 2

Comment: Unless glutathione, ascorbate molecules, peroxiredoxin, glutathione peroxidase, catalase, and superoxide dismutase enzymes to counteract ROS/RNS formation were not extant prebiotically, the basic building blocks of life would likely have been destroyed. But these enzymes are made precisely by the building blocks that these enzymes help prevent to destroy. That is a catch22 situation. 

Julie A. Reisz et.al., (2019): Mitochondrial DNA and proteins are particularly sensitive to the effects of ROS, as two dominant sources of ROS are the Electron Transport Chain complexes I and III. Furthermore, mitochondrial DNA does not have the protection of histones and has less repair machinery than exists for nuclear DNA. In the context of aging, inefficiencies in the ETC combined with the accumulation of environmental ROS exposure lead to oxidative damage of mitochondrial DNA and proteins, ultimately manifesting in a decreased capacity for efficient and robust ATP production by oxidative phosphorylation. Mitochondria are equipped with quality control machinery for the recognition of dysfunction and subsequent degradation through mitophagy. These processes are mediated by several protein complexes, including NIX (also known as BNIP3L) and Parkin/PINK1, and share in common the recognition of depolarized or damaged mitochondria. NIX plays key roles in processes such as erythropoiesis, removing mitochondria as reticulocytes develop into mature red blood cells, and in attenuating ischemia-reperfusion injury in the brain.

Another negative consequence of ROS accumulation is the activation of purine deaminases (e.g. AMP deaminase), which deplete the reservoir of high-energy phosphate purines, such as ATP. These actions also pave the way for the generation of pro-oxidants through purine catabolism, exemplified by the generation of hydrogen peroxide via xanthine oxidase. ATP depletion is particularly deleterious in that it serves as the key energy source for maintaining proteostasis balance. A lack of adequate cellular ATP supply necessitates a shift toward the preservation of the most critical processes to maintain cellular homeostasis. Increased steady-state levels of ROS coupled with diminished ATP levels exacerbate the aging quality control mechanisms that impact many aspects of proteostasis.

Folding – chaperones and endoplasmic reticulum
Proteome integrity is maintained by a network of quality control machinery responsible for the accurate translation of mRNA, polypeptide processing and folding, intracellular trafficking, and recognition and catabolism of damaged protein molecules. Chaperone proteins are specifically involved in vital roles of protein folding and transport. Disease-associated disruptions to the chaperone network have been identified, though a larger challenge lies in determining the specific mechanisms by which invading cells (e.g. cancer, viruses) hijack chaperone proteins or alter their expression. 

In mammals, the heat shock response (HSR), triggered by acute stresses such as heat, hypoxia, unfolded proteins, and the accumulation of protein aggregates (also referred to as aggresomes), utilizes the transcription factor HSF-1 to upregulate expression of heat shock proteins (Hsp) along with other proteins necessary for eliminating damaged biomolecules and restoring normal cellular function. The Hsp family of proteins are found in every cell with the cytosol, mitochondria, and endoplasmic reticulum (ER) each having a dedicated Hsp system with basal housekeeping roles in addition to stress-induction mediated by HSR. Cell types constitutively exposed to oxidative stress such as the iron-rich oxygen-carrying erythrocytes have a unique Hsp specialization, where the system mediates a “save or sacrifice” response. Hsp proteins bind to unfolded or misfolded proteins, working in conjunction with co-chaperone proteins and foldase enzymes to refold proteins in a process that often requires ATP. 

The endoplasmic reticulum (ER), home to the synthesis of membrane and secretory proteins, as well as the folding of nascent proteins translated in the ribosome, maintains its own response pathway for proteotoxic stress. The ER utilizes a more oxidizing environment than other cellular compartments that facilitates disulfide bond formation by protein disulfide isomerase (PDI) during folding. ER stress occurs in situations of unfolded protein accumulation, disruptions in cellular Ca2+ levels (as the ER maintains the largest cellular Ca2+ pool), and unbalanced oxygen homeostasis that causes hypoxia (depriving of adequate oxygen supply) or oxidative stress. The ER is equipped to remedy these acute challenges using members of the Heat shock proteins family. In addition, damaged proteins may be retro-translocated out of the ER with the help of chaperones and into the cytosol for proteasomal degradation, a process termed ER-associated protein degradation (ERAD). However, stressors that are insurmountable or that cause global disruptions to folding activate the unfolded protein response (UPR) pathway, which involves 3 transmembrane proteins that act as separate arms of the pathway and coordinate to increase the expression of ER homeostasis genes, decrease translation of other proteins to offset protein load, and expand ER size. Increased ER size does not require the activity of unfolded protein response (UPR) chaperone proteins but is selectively induced by UPR signaling. Cells whose UPR machinery cannot efficiently repair ER damage are directed to apoptosis.

Like other proteostasis mechanisms, the unfolded protein response (UPR) is adversely affected during aging by a decrease in the abundance of ER chaperone proteins (along with increased oxidative damage, increased expression of pro-apoptotic proteins, and disrupted phosphorylation status of proteins involved in translation.

Protein degradation systems
In the event of irreparable protein damage, cells employ several tools to sequester and destroy the damaged molecule to protect healthy organelles and preserve lifespan. The two systems, the ubiquitin-proteasome system (UPS) and the lysosomal-autophagy pathway, each utilizes highly coordinated networks of proteins dedicated to the recognition of damage, transport to – or synthesis of – the appropriate proteolytic organelle, and lysis of covalent protein bonds. The ubiquitin-proteasome system UPS aids in the homeostasis of short-lived cellular peptides and proteins by tagging damaged proteins with one or more ubiquitin molecules (76 amino acids) at lysine residues, then transporting labeled proteins to the 26S proteasome for degradation. Conjugation of ubiquitin moieties to protein lysines occurs in a step-wise ATP-dependent fashion facilitated by ubiquitin-activating enzymes (E1s), ubiquitin-conjugating enzymes (E2), and ubiquitin-ligating (E3) enzymes. There exist distinct proteasome forms that demonstrate preference for metabolizing mildly oxidized proteins or ubiquitinated proteins. Critically, the ubiquitination process and proteasome function are both ATP-dependent. Moreover, oxidation can inhibit ubiquitin-activating enzymes (E1s) and ubiquitin-conjugating enzymes (E2s) via modification (e.g., glutathionylation, nitrosation) of active site cysteine residues along with noted negative impacts on proteasome function. The ubiquitin-proteasome system UPS is critical for homeostasis maintenance in a variety of cell types and helps to preserve cell vitality by degrading proteins of the apoptotic machinery when they are not needed. ubiquitin-proteasome system activity is increased in stem cells, including human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) as a strategy of preserving plasticity. Recently, several E3 ubiquitin ligases were identified as elevated in hESCs compared to differentiated cells as one of the possible mechanisms underlying enhanced UPS. In the event of severe or prolonged cellular stress, the capacity of the UPS to clear ubiquitinated proteins can be exceeded. In such cases, these proteins are directed to autophagy.

The lysosomal-autophagy pathway targets misfolded proteins, ubiquitinated proteins, and larger molecular structures, such as aggresomes and even damaged organelles. There exist several types: chaperone-mediated authophagy (CMA), microautophagy, and macroautophagy. In CMA, protein chaperones assist in recognition of damaged cytosolic proteins bearing the KFERQ motif and translocation to the lysosome  (spherical vesicles that contain hydrolytic enzymes that can break down many kinds of biomolecules) surface, where they bind to protein Lamp2a and transported into the lysosome for degradation. chaperone-mediated autophagy  CMA requires the sophisticated coordination and crosstalk of many proteins. Microautophagy involves direct lysosomal absorption of smaller cellular debris, whereas macroautophagy, the dominant form referred to as simply “autophagy”, requires the synthesis of a double membrane around the damaged molecules to form an autophagosome that is later engulfed by the lysosome. The lysosome contains at least 60 unique hydrolase enzymes and maintains an acidic pH of 4.5–5 for proteolysis through the proton pump activity of vacuolar-type H+-ATPases (V-ATPases). As such, chemical integrity of the lysosome is reliant on an adequate ATP supply.

Autophagy occurs at low basal levels in cells to maintain homeostasis, and is activated in response to stresses like starvation, infection, and hypoxia. The autophagy process is indispensable for stem cell metabolism and preservation of their stemness and self-renewal properties. Expeditious activation of autophagy occurs as a result of protein post-translational modifications, of which many are known; sustained activation occurs instead through transcriptional regulation. The small molecule end-products of autophagy, including amino acids, sugars, and other metabolites, are released into the cytosol to serve as substrates in energy metabolism and other anabolic processes in an effort to maintain cellular function despite environmental or microenvironmental stressors. Autophagy activity decreases with age and is hampered in age-related diseases such as cancer. As just one of the many examples, mutation or damage to tumor suppressor protein p53 facilitates its accumulation in the cytosol, preventing its ability to activate the transcription of autophagy genes.Chaperones and proteolysis systems are profoundly affected during aging. HSR repression begins at the onset of reproductive maturity in Caenorhabditis elegans (C. elegans) via epigenetic modification of histone H3. Both the UPS and the lysosomal system have diminished proteolysis capacities in aging organisms and their protein machineries are each susceptible to aging-related damage through oxidation, conjugation to lipid peroxidation products, and/or protein cross-linking. Though spatially distinct, the lysosome and proteasome are interrelated and have been shown to compensate, at least partially, when one is compromised. One example of this interplay was revealed in a study earlier this year of N-terminal arginylation, in which arginine is added to specific residues of protein N-termini exposed by endopeptidase activity. Though a comprehensive picture of the cellular consequences of arginylation is not yet established, experiments in this study found that proteins containing this modification are detected by N-recognins that direct the protein to the UPS or, when the UPS is inhibited or compromised, by p62 with resulting autophagy. Such observations illustrate compensatory mechanisms within proteostasis and how damaged or dysfunctional proteins may be processed differentially in context-dependent manners. Further illustrating the interconnections between these two proteolytic hubs, the transcription factor homeodomain-interacting protein kinase 1 (HPK-1) was recently identified as preserving proteostasis in C. elegans by both suppressing an inhibitory post-translational modification to HSF-1 and, separately, by regulating the expression of genes involved in the autophagy pathway, particularly autophagosome formation




1. Julie A. Reisz: When nature’s robots go rogue: exploring protein homeostasis dysfunction and the implications for understanding human aging disease pathologies 2019 Apr 1
2. Jie Xu et.al., : Reactive oxygen species at the oxide/water interface: Formation mechanisms and implications for prebiotic chemistry and the origin of life 26 January 2013

Molecular robots: By design, or not design? 

Lifu Song (2017): Similar to the electric robots, microbial cells can be considered as a kind of “biological robots” that can sense the information of fast-changing environment, compute and make decisions for survival. Cells are highly programmable as proved by recent developments in synthetic biology. Programming cells to perform specific tasks have been achieved successfully in many cases. For example, cells have been programmed to produce pharmaceuticals, fuels, amino acids, fine and bulk chemicals and even metal nanoparticles. Cells also have been programmed to sense toxic compounds in environments, to record the environment signal in human gut and to eradicate human pathogen. Although the capability of a single cell is limited, cells can reproduce themselves exponentially and work simultaneously to solve complicated tasks or accomplish sophisticated tasks in principle. However, these capabilities of cells have not yet been well exploited. 1

The basic idea is to program the cells to perform a certain screening task which is linked to the desired property or activity of the molecule of interest. We then engineer the host cells so that they can screen for phages carrying the targets with desired properties. We then design an intracellular biological circuit to control the infectivity of packaged phages. We demonstrated that the biological ‘robots’, i.e. the cells, can be engineered to perform screening tasks in protein engineering. 

Comment: It is evident, that the researchers resort to their engineering skills and design capabilities based on their intelligence to repurpose the cells to perform intended tasks and not evolutionary algorithms. Why? Because intelligence is a superior agent to achieve intended goals and purposeful functions, rather than unguided nonintelligent evolutionary mechanisms. We, equipped with intelligence, routinely create robots, computer programs, and engineering devices that accomplish complicated and sophisticated tasks. We do not concede the same power to non-intelligent mechanisms, simply because we know intelligence is superior to instantiate these things. Time does not help in this scenario. Evolution is only a powerful mechanism, when sold as such by proponents and evolutionary story-tellers. But that seems not to be much related to reality. 

S. Ornes (2022): The human body is a “biological machine” powered by living parts. Cells already “know” how to sense their environment, work together and respond to the world around them. If scientists can harness that knowledge in biological materials, then they could build artificial systems with the same traits. Materials like concrete and metal don’t replicate or fix themselves. They don’t break down quickly in the environment, either. But cells do: They self-renew and can often heal themselves. They continue working as long as they have food to fuel them. “Imagine you can fabricate structures that can grow or heal themselves — do all the things that we find around us from [the] biological world 2

Comment: The technological solutions employed in cells are light-years more sophisticated and advanced than anything ever created by man. Man-made artifacts are obviously designed. Why are things, far more advanced and elaborated, not designed?

 

1. Lifu Song: Engineering ‘cell robots’ for parallel and highly sensitive screening of biomolecules under in vivo conditions  09 November 2017
2. Stephen Ornes: Robots made of cells blur the line between creature and machine March 31, 2022