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Peptide bonding of amino acids to form proteins and its origins

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Peptide bonding of amino acids to form proteins and its origins

Primary Structure: Amino Acids Are Linked by Peptide Bonds to Form Polypeptide Chains
Proteins are linear polymers formed by linking the alpha-carboxyl group of one amino acid to the a-amino group of another amino acid. This type of linkage is called alpha peptide bond or an amide bond. The formation of a dipeptide from two amino acids is accompanied by the loss of a water molecule. The equilibrium of this reaction lies on the side of hydrolysis rather than synthesis under most conditions. Hence, the biosynthesis of peptide bonds requires an input of free energy. Nonetheless, peptide bonds are quite stable kinetically because the rate of hydrolysis is extremely slow; the lifetime of a peptide bond in aqueous solution in the absence of a catalyst approaches 1000 years.

A series of amino acids joined by peptide bonds form a polypeptide chain, and each amino acid unit in a polypeptide is called a residue. A polypeptide chain has directionality because its ends are different: an alpha -amino group is present at one end and an a -carboxyl group at the other. The amino end is taken to be the beginning of a polypeptide chain; by convention, the sequence of amino acids in a polypeptide chain is written starting with the amino-terminal residue. 12

Question: By the convention of whom ??!!

Thus, in the polypeptide Tyr-Gly-Gly-Phe- Leu (YGGFL), tyrosine is the amino-terminal (N-terminal) residue and leucine is the carboxyl-terminal (C-terminal) residue . Leu- Phe-Gly-Gly-Tyr (LFGGY) is a different polypeptide, with different chemical properties.

Amino acid sequences have direction. 
This illustration of the pentapeptide Tyr-Gly-Gly-Phe-Leu (YGGFL) shows the sequence from the amino terminus to the carboxyl terminus. This pentapeptide, Leu-enkephalin, is an opioid peptide that modulates the perception of pain. The reverse pentapeptide, Leu-Phe-Gly-Gly-Tyr (LFGGY), is a different molecule and has no such effects.

A polypeptide chain consists of a regularly repeating part, called the main chain or backbone, and a variable part, comprising the distinctive side chains (Figure below).

Components of a polypeptide chain. 
A polypeptide chain consists of a constant backbone (shown in black) and variable side chains (shown in green).

The polypeptide backbone is rich in hydrogen-bonding potential. Each residue contains a carbonyl group (C = O), which is a good hydrogen-bond acceptor, and, with the exception of proline, an NH group, which is a good hydrogen-bond donor. These groups interact with each other and with functional groups from side chains to stabilize particular structures

Peptidyl transferase catalyzes peptide-bond synthesis
A molecule called the Peptidyl Transferase Center (PTC) is considered by some as having an essential role in the emergence of life, since this catalytic ability to get together amino acids is crucial for protein synthesis and thus, for the first transition from an RNA world to a Ribonucleoprotein world, as seen in modern organisms.

All known cellular organisms have the PTC conserved and the process of reading the information contained in the messenger RNA, in general, is similar in all life forms. Would the common ancestor of all life forms be a part of the largest subunit of the ribosomal RNA? When thinking about LUCA as a molecule, and more specifically, as the large subunit of the ribosome or even more specifically as the PTC, there is an extensive modification into the junction point on which all living organisms came to be. Here the nature of LUCA is changed since it places the common point of origin in a time where the RNA was the information-carrying molecule and the cellular systems were still starting to maturate. 10

The ribosome accelerates peptide bond formation by lowering the activation entropy of the reaction due to positioning the two substrates, ordering water in the active site, and providing an electrostatic network that stabilizes the reaction intermediates. Proton transfer during the reaction appears to be promoted by a concerted proton shuttle mechanism that involves ribose hydroxyl groups on the tRNA substrate. 11

Positioning, ordering, providing, stabilizing, promoting a concerted shuttle mechanism are all tasks which we can easily attribute to the action of an intelligence, but could hardly emerge without external direction by random unguided events.

Protein synthesis in the cell is performed on ribosomes, large ribonucleoprotein particles that consist of three RNA molecules and more than 50 proteins. Ribosomes are composed of two subunits, the larger of which has a sedimentation coefficient of 50S in prokaryotes (the 50S subunit) and the smaller which sediments at 30S (the 30S subunit); together they form 70S ribosomes. The ribosome is a molecular machine that selects its substrates, aminoacyl-tRNAs (aa-tRNAs) d , rapidly and accurately and catalyzes the synthesis of peptides from amino acids. The 30S subunit contains the decoding site, where base-pairing interactions between the mRNA codon and the tRNA anticodon determines the selection of the cognate aa-tRNA.

The large ribosomal subunit contains the site of catalysis—the peptidyl transferase (PT) center—which is responsible for making peptide bonds during protein elongation and for the hydrolysis of peptidyl-tRNA (pepttRNA) during the termination of protein synthesis. The ribosome has three tRNA binding sites: A, P, and E sites ( figure below )

Schematic of Peptide Bond Formation on the Ribosome
The a-amino group of aminoacyl-tRNA in the A site (red) attacks the carbonyl carbon of the pept-tRNA in the P site (blue) to produce a new, one amino acid longer pept-tRNA in the A site and a deacylated tRNA in the P site. The 50S subunit, where the PT center is located, is shown in light gray and the 30S subunit in dark gray. A, P, and E sites of the ribosome are indicated.

During the elongation cycle of protein synthesis, aa-tRNA is delivered to the A site of the ribosome in a ternary complex e with elongation factor Tu (EF-Tu) c and GTP. Following GTP hydrolysis and release from EF-Tu, aa-tRNA accommodates in the A site of the Peptidyl Transferase Center ( PT center ) and reacts with pept-tRNA bound to the P site, yielding deacylated tRNA in the P site and A site pept-tRNA that is extended by one amino acid residue. The subsequent movement of tRNAs and mRNA through the ribosome (translocation) is catalyzed by another elongation factor (EF-G in bacteria). During translocation, pept-tRNA and deacylated tRNA move to the P and E sites, respectively; a new codon is exposed in the A site for the interaction with the next aa-tRNA, and the deacylated tRNA is released from the E site.

The movement of aa-tRNA into the A site is a multistep process that requires structural rearrangements of the ribosome, EF-Tu, and aa-tRNA.

Structure of the Active Site of the Peptidyl Transferase Center (PTC)
50S subunits are composed of two rRNA molecules, 23S rRNA and 5S rRNA, and more than 30 proteins (Figure A below).

Structure of the Peptidyl Transferase Center
(A) Crystal structure of the 50S subunit from H. marismortui with a transition state analog (red) bound to the active site. Ribosomal proteins are blue, the 23S rRNA backbone is brown, the 5S rRNA backbone is olive, and
rRNA bases are pale green. 
(B) Substrate binding to the active site. Base pairs formed between cytosine residues of the tRNA analogs in the A site (yellow) and P site (orange) with 23S rRNA bases (pale green) are indicated. The a-amino group of the A site substrate (blue) is positioned for the attack on the carbonyl carbon of the ester linking the peptide moiety of the P site substrate (green). Inner shell nucleotides are omitted for clarity.

The Mechanism of Peptide Bond Formation
The combined evidence supports the idea that peptide bond formation on the ribosome is driven by a favorable entropy change. The A and P site substrates are precisely aligned in the active center by interactions of their CCA sequences and of the nucleophilic a-amino group with residues of 23S rRNA in the active site. The most favorable catalytic pathway involves a six-membered transition state (Figure below) in which proton shuttling occurs via the 20-OH of A76 of the P site tRNA. The reaction does not involve chemical catalysis by ribosomal groups but may be modulated by conformational changes at the active site which can be induced by protonation.

Concerted Proton Shuttle Mechanism of Peptide Bond Formation
Pept-tRNA (P site) and aminoacyl-tRNA (A site) are blue and red, respectively, ribosome residues are pale green, and ordered water molecules are gray. The attack of the a-NH2 group on the ester carbonyl carbon results in a six-membered transition state in which the 20-OH group of the A site A76 ribose moiety donates its proton to the adjacent leaving 30 oxygen and simultaneously receives a proton from the amino group. Ribosomal residues are not involved in chemical catalysis but are part of the H bond network that stabilizes the transition state.

In addition to placing the reactive groups into close proximity and precise orientation relative to each other, the ribosome appears to work by providing an electrostatic environment that reduces the free energy of forming the highly polar transition state, shielding the reaction against bulk water, helping the proton shuttle forming the leaving group or a combination of these effects. With this preorganized network, the ribosome avoids the extensive solvent reorganization that is inevitable in the corresponding reaction in solution, resulting in significantly more favorable entropy of activation of the reaction on the ribosome.

With both the P site and the A site occupied by aminoacyl-tRNA, the stage is set for the formation of a peptide bond: the formylmethionine molecule linked to the initiator tRNA will be transferred to the amino group of the amino acid in the A site. The formation of the peptide bond, one of the most important reactions in life, is a thermodynamically spontaneous reaction catalyzed by a site on the 23S rRNA of the 50S subunit called the peptidyl transferase center. This catalytic center is located deep in the 50S subunit near the tunnel that allows the nascent peptide to leave the ribosome. The ribosome, which enhances the rate of peptide bond synthesis by a factor of 10^7 over the uncatalyzed reaction, derives much of its catalytic power from catalysis by proximity and orientation. The ribosome positions and orients the two substrates so that they are situated to take advantage of the inherent reactivity of an amine group (on the aminoacyl-tRNA in the A site) with an ester (on the initiator tRNA in the P site). The amino group of the aminoacyl-tRNA in the A site, in its unprotonated state, makes a nucleophilic attack on the ester linkage between the initiator tRNA and the formylmethionine molecule in the P site (Figure A below). 

Peptide-bond formation.
(A) The amino group of the aminoacyl-tRNA attacks the carbonyl group of the ester linkage of the peptidyl-tRNA. 
(B) An eight-membered transition state is formed. Note: Not all atoms are shown and some bond lengths are exaggerated for clarity.
(C) This transition state collapses to form the peptide bond and release the deacylated tRNA.

The nature of the transition state that follows the attack is not established and several models are plausible. One model proposes roles for the 2' OH of the adenosine of the tRNA in the P site and a molecule of water at the peptidyl transferase center (Figure B above). The nucleophilic attack of the a-amino group generates an eight-membered transition state in which three protons are shuttled about in a concerted manner. The proton of the attacking amino group hydrogen bonds to the 2' oxygen of ribose of the tRNA. The hydrogen of 2' OH, in turn, interacts with the oxygen of the water molecule at the center, which then donates a proton to the carbonyl oxygen. A collapse of the transition state with the formation of the peptide bond allows protonation of the 3'OH of the now empty tRNA in the P site (Figure C above). The stage is now set for translocation and formation of the next peptide bond.

The formation of a peptide bond is followed by the GTP-driven a translocation of tRNAs and mRNA
With the formation of the peptide bond, the peptide chain is now attached to the tRNA whose anticodon is in the A site on the 30S subunit. The two subunits rotate with respect to one another, and this structural change places the CCA b end of the same tRNA and its peptide in the P site of the large subunit (Figure below). 

Mechanism of protein synthesis. 
The cycle begins with peptidyltRNA in the P site. 
(1) An aminoacyl-tRNA binds in the A site. 
(2) With both sites occupied, a new peptide bond is formed.
(3) The tRNAs and the mRNA are translocated through the action of elongation factor G, which moves the deacylated tRNA to the E site. 
(4) Once there, the tRNA is free to dissociate to complete the cycle.

Another aminoacyl-tRNA arrives and binds at the A site (1). Again, peptide bond synthesis occurs (2). However, protein synthesis cannot continue without the translocation of the mRNA and the tRNAs within the ribosome. Elongation factor G (EF-G, also called translocase) c catalyzes the movement of mRNA, at the expense of GTP hydrolysis, by a distance of three nucleotides. Now, the next codon is positioned in the A site for interaction with the incoming aminoacyl-tRNA (3). The peptidyl- tRNA moves out of the A site into the P site on the 30S subunit and at the same time, the deacylated tRNA moves out of the P site into the E site and is subsequently released from the ribosome (4). The movement of the peptidyl-tRNA into the P site shifts the mRNA by one codon, exposing the next codon to be translated in the A site.

The three-dimensional structure of the ribosome undergoes significant change during translocation, and evidence suggests that translocation may result from properties of the ribosome itself. However, EF-G accelerates the process. A possible mechanism for accelerating the translocation process is shown in Figure below.

Translocation mechanism. 
In the GTP form, EF-G binds to the A site on the 50S subunit. This binding stimulates GTP hydrolysis, inducing a conformational change in EF-G that forces the tRNAs and mRNA to move through the ribosome by a distance corresponding to one codon.

Question: How did unguided random processes select and finely tune the forces to move the tRNAs and mRNA by the right distance of one codon?

EF-G in the GTP form binds to the ribosome near the A site, interacting with the 23S rRNA of the 50S subunit. The binding of EF-G to the ribosome stimulates the GTPase activity of EF-G. On GTP hydrolysis, EF-G undergoes a conformational change that displaces the peptidyl-tRNA in the A site to the P site, which carries the mRNA and the deacylated tRNA with it. The dissociation of EF-G leaves the ribosome ready to accept the next aminoacyl-tRNA into the A site. Note that the peptide chain remains in the P site on the 50S subunit throughout this cycle, growing into the exit tunnel. This cycle is repeated, with mRNA translation taking place in the 5' ==>> 3' direction, as new aminoacyl-tRNAs move into the A site, allowing the polypeptide to be elongated until a stop signal is found.

The direction of translation has important consequences. Transcription also is in the 5' ==>> 3' direction. If the direction of translation were opposite that of transcription, only fully synthesized mRNA could be translated. In contrast, because the directions are the same, mRNA can be translated while it is being synthesized.

Question: How could natural, unguided, random processes select the right direction to be translated? Trial and error ?

In bacteria, almost no time is lost between transcription and translation. The 5' end of mRNA interacts with ribosomes very soon after it is made, well before the 3' end of the mRNA molecule is finished. An important feature of bacterial gene expression is that translation and transcription are closely coupled in space and time.

There is a huge gap that has to be filled between " modern " polypeptide formation through ribosomes, mRNA, and tRNA's, and supposed primordial amino chain formations without this advanced machinery. How could the gap be closed? Not only are prebiotic mechanisms unlikely, but the transition would require the emergence of all the complex machinery and afterward transition from one mechanism to the other. Tamura admits that fact clearly: the ultimate route to the ribosome remains unclear.   It takes a big leap of faith to believe, that could be possible in any circumstances. 

Mystery of Life's Origin 4
Experimental evidence indicates that if there are bonding preferences between amino acids, they are not the ones found in natural organisms. There are three basic requirements for a biologically functional protein.

One: It must have a specific sequence of amino acids. At best prebiotic experiments have produced only random polymers. And many of the amino acids included are not found in living organisms.

Second: An amino acid with a given chemical formula may in its structure be either “righthanded” (D-amino acids) or “left-handed” (L-amino acids). Living organisms incorporate only L-amino acids. However, in prebiotic experiments where amino acids are formed approximately equal numbers of D- and L-amino acids are found. This is an “intractable problem” for chemical evolution (p. vi).

Third: In some amino acids there are more positions than one on the molecule where the amino and carboxyl groups may join to form a peptide bond. In natural proteins only alpha-peptide bonds (designating the location of the bond) are found. In proteinoids, however, beta, gamma and epsilon peptide bonds largely predominate. Just the opposite of what one would expect if bonding preferences played a role in prebiotic evolution.

Studies of peptide bond formation in the absence of modern biological machinery can give insight into the mechanism employed by the ribosome’s active site, as well as yield important information in the prebiotic route to the first peptides in the origin of life. The formation of a peptide bond (reaction R1 shown below) is a condensation reaction, eliminating a water molecule for each peptide bond formed, and thus faces both thermodynamic and kinetic constraints in bulk aqueous solution

Amino Acids joined together through a dehydration reaction, where a water molecule is formed and removed to form a covalent bond called a peptide bond. A structure resulting from a bunch of these bonds repeating over and over is called a polypeptide. Like DNA molecules, polypeptides have a direction: they’ve got an amino acid at one end (the N-terminus) and a carboxyl group at the other (the C-terminus).

In modern biology, the condensation reactions necessary in the formation of peptide bonds are facilitated catalytically by the large subunit of the ribosome.

Fazale Rana's Cell's design: The chemical reactions that form the bonds that join amino acids together in polypeptide chains are catalyzed or assisted by ribosomes. The ribosome, mRNA, and tRNA molecules work cooperatively to produce proteins. Using an assembly-line process, protein manufacturing machinery forms the polypeptide chains (that constitute proteins) one amino acid at a time. This protein synthetic apparatus joins together three to five amino acids per second. Ribosomes, in conjunction with mRNA and tRNAs, assemble the cell's smallest proteins, about one hundred to two hundred amino acids in length, in less than one minute. The processing of proteins in the lumen (posttranslational modification) is quite extensive. Posttranslational modifications include (1) formation and reshuffling of disulfide bonds (these bonds form between the side chains of cysteine amino acid residues within a protein, stabilizing its three-dimensional structure)

Amino Acids Are Added to the C-terminal End of a Growing Polypeptide Chain
Each amino acid is first coupled to specific tRNA molecules, next is the mechanism that joins these amino acids together to form proteins. The fundamental reaction of protein synthesis is the formation of a peptide bond between the carboxyl group at the end of a growing polypeptide chain and a free amino group on an incoming amino acid. Consequently, a protein is synthesized stepwise from its N-terminal end to its C-terminal end. Throughout the entire process, the growing carboxyl end of the polypeptide chain remains activated by its covalent attachment to a tRNA molecule (forming a peptidyl-tRNA). Each addition disrupts this high-energy covalent linkage, but immediately replaces it
with an identical linkage on the most recently added amino acid

The incorporation of an amino acid into a protein. A polypeptide chain grows by the stepwise addition of amino acids to its C-terminal end. The formation of each peptide bond is energetically favorable because the growing C-terminus has been activated by the covalent attachment of a tRNA molecule. The peptidyl-tRNA linkage that activates the growing end is regenerated during each addition. The amino acid side chains have been abbreviated as R1, R2, R3, and R4; as a referencepoint, all of the atoms in the second amino acid in the polypeptide chain are shaded gray. The figure shows the addition of the fourth amino acid (red) to the growing chain.

Peptide Bond Formation: RNA's Big Bang

The genetic code may have been established gradually (Wong, 1975). 5

observe the " may have's ", by some means, might have, proposed the idea, would have,

The second law of thermodynamics indicates that peptide bond formation does not occur spontaneously. Therefore, energy must be added into the system by some means and amino acids must be "activated." Modern biological systems use the energy of the ATP hydrolysis for coupling many reactions (Lipmann, 1941). However, during the prebiotic stage, the light from the sun, geothermal energy, pressure in the thermal vent, or other similar sources may have been used in the process of activating the molecules of a system. The development of prebiotic precursors of biomolecules might have occurred in interstellar space, and were subsequently transferred to Earth by comets, asteroids, or meteorites (Oró, 1961; Chyba et al., 1990; Chyba & Sagan, 1992). Reactions on clay (Paecht-Horowitz et al., 1970) and/or dry mixtures of amino acids (Fox & Harada, 1958) may have facilitated the condensation of activated amino acids, thereby forming peptide bonds. Iron sulfate is known to cause unusual reducing reactions, especially with H2S. Wächtershäuser (1992) previously proposed the idea of an "iron-sulfur world" where low-molecular weight constituents may have originated autotrophic metabolism. In such circumstances, amino acids would have been converted into simple peptides (Huber & Wächtershäuser, 1998). In fact, it has been demonstrated that the peptide containing a thioester at the carboxyl-terminal undergoes nucleophilic attack by the side chain of the Cys residue at the amino terminal of another peptide. Moreover, the formed thioester ligation product readily undergoes a rapid intramolecular reaction at the α-amino group of the Cys to yield a product with a native peptide bond. This series of events is called "native chemical ligation" and is important in the general application of protein chemistry (Dawson et al., 1994). These possibilities should be further considered in terms of the very early mechanisms responsible for peptide bond formation. However, because we must consider the modern ribosome, we cannot avoid consideration of RNA in the evolution of biological systems.

Its remarkable how mainstream scientific papers give to their naturalistic proposals a positive connotation, but without providing compelling evidence for their assertions.

The Emergence of Information-Rich Biopolymers 1
Given an ocean full of small molecules of the types likely to be produced on a prebiological earth with the types of processes postulated by origin of life enthusiasts, we must next approach the question of polymerization. This question poses a two edged sword: we must first demonstrate that macromolecule synthesis is possible under prebiological conditions, then we must construct a rationale for generating macromolecules rich in the information necessary for usefulness in a developing precell. We shall deal with these separately.

The synthesis of proteins and nucleic acids from small molecule precursors represents one of the most difficult challenges to the model of prebiological evolution. There are many different problems confronted by any proposal. Polymerization is a reaction in which water is a product. Thus it will only be favored in the absence of water. The presence of precursors in an ocean of water favors depolymerization of any molecules that might be formed. Careful experiments done in an aqueous solution with very high concentrations of amino acids demonstrate the impossibility of significant polymerization in this environment.

Polymer formation in aqueous environments would most likely have been necessary on early Earth because the liquid ocean would have been the reservoir of amino acid precursors needed for protein synthesis. 3

A thermodynamic analysis of a mixture of protein and amino acids in an ocean containing a 1 molar solution of each amino acid (100,000,000 times higher concentration than we inferred to be present in the prebiological ocean) indicates the concentration of a protein containing just 100 peptide bonds (101 amino acids) at equilibrium would be 10-338 molar. Just to make this number meaningful, our universe may have a volume somewhere in the neighborhood of 10^85 liters. At 10-338 molar, we would need an ocean with a volume equal to 10229 universes (100, 000, 000, 000, 000, 000, 000, 000, 000, 000, 000, 000, 000, 000, 000, 000, 000, 000, 000, 000, 000, 000, 000, 000, 000, 000, 000, 000, 000, 000, 000, 000, 000, 000, 000, 000, 000, 000, 000, 000, 000, 000, 000, 000, 000, 000, 000, 000, 000, 000, 000, 000, 000, 000, 000, 000, 000, 000, 000, 000, 000, 000, 000, 000, 000, 000, 000, 000, 000, 000, 000, 000) just to find a single molecule of any protein with 100 peptide bonds. So we must look elsewhere for a mechanism to produce polymers. It will not happen in the ocean.

Sidney Fox, an amino acid chemist, and one of my professors in graduate school, recognized the problem and set about constructing an alternative. Since water is unfavorable to peptide bond formation, the absence of water must favor the reaction. Fox attempted to melt pure crystalline amino acids in order to promote peptide bond formation by driving off water from the mix. He discovered to his dismay that most amino acids broke down to a tarry degradation product long before they melted. After many tries, he discovered two of the 20 amino acids, aspartic and glutamic acid, would melt to a liquid at about 200oC. He further discovered that if he were to dissolve the other amino acids in the molten aspartic and glutamic acids, he could produce a melt containing up to 50% of the remaining 18 amino acids. It was no surprise then that the amber liquid, after cooking for a few hours, contained polymers of amino acids with some of the properties of proteins. He subsequently named the product proteinoids. The polymerized material can be poured into an aqueous solution, resulting in the formation of spherules of protein-like material which Fox has likened to cells. Fox has claimed nearly every conceivable property for his product, including that he had bridged the macromolecule to cell transition. He even went so far as to demonstrate a piece of lava rock could substitute for the test tube in proteinoid synthesis and claimed the process took place on the primitive earth on the flanks of volcanoes. However, his critics, as well as his own students, have stripped his credibility. Note the following problems:

1) Proteinoids are not proteins; they contain many non-peptide bonds and unnatural cross-linkages.

2) The peptide bonds they do contain are beta bonds, whereas all biological peptide bonds are alpha.

3) His starting materials are purified amino acids bearing no resemblance to the materials available in the "dilute soup." If one were to try the experiment with condensed "prebiological soup," tar would be the only product.

4) The ratio of 50% Glu and Asp necessary for success in these experiments bears no resemblance to the vastly higher ratio of Gly and Ala found in nearly all primitive earth synthesis experiments.

5) There is no evidence of information contained in the molecules.

All of his claims have failed the tests of rationality when examined carefully. As promising as his approach seemed in theory, the reality is catastrophic to the hopes of paleobiogeochemists.

A number of other approaches have been tried. The most optimistic of these is the use of clays. Clays are very thin, very highly ordered arrays of complex aluminum silicates with numerous other cations. In this environment, the basic amino groups tend to order and polymers of several dozen amino acids have been produced. While these studies have generated enthusiastic interest on the part of prebiological evolutionists, their relevance is quickly dampened by several factors.

1) While ordered amino acids joined by peptide bonds result, the product contains no meaningful information.

2) The clays exhibit a preference for basic amino acids.

3) No polymerization of amino acids results if free amino acids are used.

4) Pure activated amino acids attached to adenine must be used in order to drive the reaction toward polymerization. Adenylated amino acids are not exactly the most likely substrate to be floating about the prebiological ocean.

5) The resultant polymers are three dimensional rather than linear, as is required for biopolymers.

At least one optimistic scientist (Cairns-Smith, 1982) believes that the clay particles themselves formed the substance of the first organisms! In reality, the best one can hope for from such a scenario is a racemic polymer of proteinous and non-proteinous amino acids with no relevance to living systems.

           A final chapter has recently been opened with the discovery of autocatalytic RNA molecules. These were originally received with great excitement by the prebiological evolutionists because they gave hope of alleviating the need to make proteins in the first cell. These so-called "ribozymes" proved incapable of rising to the occasion, however, for not only are the molecules themselves very limited in what they have been shown capable of doing, but the production of the precursors of RNA by any prebiological mechanism considered thus far is a problem at least as difficult as the one ribozymes purport to solve:

1) While ribose can be produced under simulated prebiological conditions via the formose reaction, it is a rare sugar in formaldehyde polymers (the prebiological mechanism believed to have given rise to sugars). In addition the presence of nitrogenous substances such as amino acids in the reaction mixture would prevent sugar synthesis (Shapiro, 1988). Cairns-Smith (1993) has summarized the situation as follows:"Sugars are particularly trying. While it is true that they form from formaldehyde solutions, these solutions have to be far more concentrated than would have been likely in primordial oceans. And the reaction is quite spoilt in practice by just about every possible sugar being made at the same time - and much else besides. Furthermore the conditions that form sugars also go on to destroy them. Sugars quickly make their own special kind of tar - caramel - and they make still more complicated mixtures if amino acids are around."

2) When produced and condensed with a nucleotide base, a mixture of optical isomers results, only one of which is relevant to prebiological studies.

3) Polymerization of nucleotides is inhibited by the incorporation of such an enantiomorph.

4) While only 3'-5' polymers occur in biological systems, 5'-5' and 2'-5' polymers are favored in prebiological type synthetic reactions (Joyce and Orgel, 1993, but see Usher,et. al. for an interesting sidelight).

5) None of the 5 bases present in DNA/RNA are produced during HCN oligomerization in dilute solutions (the prebiological mechanism believed to give rise to nucleotide bases). And many other non-coding bases would compete during polymerization at higher concentrations of HCN.

In addition to the problems of synthesis of the precursors and the polymerization reactions, the whole scheme is dependent on the ability to synthesize an RNA molecule which is capable of making a copy of itself, a feat that so far has eluded strenuous efforts. The molecule must also perform some function vital to initiating life force. So far all of this talk of an "RNA World" remains wishful thinking best categorized as fiction. The most devastating indictment of the scheme however, is that it offers no clue as to how one gets from such a scheme to the DNA-RNA-Protein mechanism of all living cells. The fact that otherwise rational scientists would exhibit such rampant enthusiasm for this scheme so quickly reveals how little faith they have in all other scenarios for the origin of life, including the ones discussed above.

Guanosine triphosphate ( GTP) is a high energy nucleotide (not to be confused with nucleoside) found in the cytoplasm or polymerised to form the guanine base. 17 It is a result of it's complex three dimensional structure and the variety of different chemical groups which it comprises of. 
Guanosine-5'-triphosphate (GTP) is a purine nucleoside triphosphate. It is one of the building blocks needed for the synthesis of RNA during the transcription process. Its structure is similar to that of the guanine nucleobase, the only difference being that nucleotides like GTP have a ribose sugar and three phosphates, with the nucleobase attached to the 1' and the triphosphate moiety attached to the 5' carbons of the ribose. It also has the role of a source of energy or an activator of substrates in metabolic reactions, like that of ATP, but more specific. It is used as a source of energy for protein synthesis and gluconeogenesis. GTP is essential to signal transduction, in particular with G-proteins, in second-messenger mechanisms where it is converted to guanosine diphosphate (GDP) through the action of GTPases. 16

Guanosine is a purine nucleoside comprising guanine attached to a ribose (ribofuranose) ring via a β-N9-glycosidic bond. Guanosine can be phosphorylated to become guanosine monophosphate (GMP), cyclic guanosine monophosphate (cGMP), guanosine diphosphate (GDP), and guanosine triphosphate (GTP). These forms play important roles in various biochemical processes such as synthesis of nucleic acids and proteins, photosynthesis, muscle contraction, and intracellular signal transduction (cGMP). 18

For the synthesis purines, following enzymes are required:

phosphoribosylamine-glycine ligase,
phosphoribosylglycinamide formyltransferase,
phosphoribosylformylglycinamidine synthase,
phosphoribosylformylglycinamidine cyclo-ligase, 20

Guanine is one of the four main nucleobases found in the nucleic acids DNA and RNA. 
For scientists attempting to understand how the building blocks of RNA originated on Earth, guanine -- the G in the four-letter code of life -- has proven to be a particular challenge. While the other three bases of RNA -- adenine (A), cytosine (C) and uracil (U) -- could be created by heating a simple precursor compound in the presence of certain naturally occurring catalysts, guanine had not been observed as a product of the same reactions.

How could and would random events attach a phosphate group to the right position of a ribose molecule to provide the necessary chemical activity? And how would non-guided random events be able to attach the nucleic bases to the ribose?  The coupling of a ribose with a nucleotide is the first step to form RNA, and even those engrossed in prebiotic research have difficulty envisioning that process, especially for purines and pyrimidines.”
The sugar found in the backbone of both DNA and RNA, ribose, has been particularly problematic, as the most prebiotically plausible chemical reaction schemes have typically yielded only a small amount of ribose mixed with a diverse assortment of other sugar molecules. 16

Glycosidic bond
The formation of nucleosides in abiotic conditions is a major hurdle in origin-of-life studies. The formamido pyrimidine-based syntheses are high regioselective, moderately stereoselective, multi-step, only apply to purines and afford a mixture of furanosides and pyranosides. The prebiotic worth of these syntheses is inversely proportional to the procedural complexities involved, requiring numerous concentration, purification and supplementation steps, designed to specifically overcome intermediate reactions bottlenecks. 21

Guanosine monophosphate (GMP)

b CCA is a terminal sequence required for the function of all tRNAs, is added to the 3' ends of tRNA molecules for which this terminal sequence is not encoded in the DNA. The enzyme that catalyzes the addition of CCA is atypical for an RNA polymerase in that it does not use a DNA template. A third type of processing is the modification of bases and ribose units of ribosomal RNAs. 6 CCA is added by the CCA-adding enzyme (Figure below).

Transfer RNA precursor processing. 
The conversion of a yeast tRNA precursor into a mature tRNA requires the removal of a 14-nucleotide intron (yellow), the cleavage of a 59 leader (green), and the removal of UU and the attachment of CCA at the 39 end (red). In addition, several bases are modified.

Eukaryotic tRNAs are also heavily modified on base and ribose moieties; these modifications are important for function. In contrast with prokaryotic tRNAs, many eukaryotic pre-tRNAs are also spliced by an endonuclease and a ligase to remove an intron.

tRNA nucleotidyltransferase adds the invariant CCA terminus to the tRNA 30-end, a central step in tRNA maturation.7

Protein synthesis takes place in cytosolic ribosomes, mitochondria (mitoribosomes), and in plants, the plastids (chloroplast ribosomes). Each of these compartments requires a complete set of functional tRNAs to carry out protein synthesis. The production of mature tRNAs requires processing and modification steps such as the addition of a 3’-terminal cytidine-cytidine-adenosine (CCA). Since no plant tRNA genes encode this particular sequence, a tRNA nucleotidyltransferase must add this sequence post-transcriptionally and therefore is present in all three compartments. 8

c  EF-G (elongation factor G, historically known as translocase) is involved in protein translation. As a GTPase, EF-G catalyzes the movement (translocation) of transfer RNA (tRNA) and messenger RNA (mRNA) through the ribosome. EF-G is made up of 704 amino acids that form 5 domains, labeled Domain I through Domain V. 9

d The joining of an amino acid to a tRNA molecule to form an aminoacyl-tRNA is catalyzed by a specific enzyme called an Aminoacyl tRNA synthetase 14An aminoacyl-tRNA synthetase (aaRS or ARS), also called tRNA-ligase, is an enzyme that attaches the appropriate amino acid onto its tRNA. It does so by catalyzing the esterification of a specific cognate amino acid or its precursor to one of all its compatible cognate tRNAs to form an aminoacyl-tRNA. In humans, the 20 different types of aa-tRNA are made by the 20 different aminoacyl-tRNA synthetases, one for each amino acid of the genetic code. This is sometimes called "charging" or "loading" the tRNA with the amino acid. Once the tRNA is charged, a ribosome can transfer the amino acid from the tRNA onto a growing peptide, according to the genetic code. Aminoacyl tRNA therefore plays an important role in RNA translation, the expression of genes to create proteins. 13

e ternary complex is a protein complex containing three different molecules that are bound together.  15

6. Styer, Biochemistry, 8th. edition, page 870
12. Styer, Biochemistry, 8th. edition, page 36

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Formation of amide bonds without a condensation agent and implications for origin of life 2

AMIDE bonds are of central importance for biochemistry; in the guise of peptide bonds, they form the backbone of proteins. The formation of amide bonds without the assistance of enzymes poses a major challenge for theories of the orgin of life. Enzyme-free formation of amide bonds between amino acids has been demonstrated in the presence of condensing agents such as cyanamide1–4. Here we report the formation of amide bonds in aqueous solution in the absence of any condensing agent. We find that the formation of pyrite (FeS2) from FeS and H2S can provide the driving force for reductive acetylation of amino acids with mercaptoacetic acid (HSCH2COOH). The redox energy of pyrite formation permits the activation of the carboxylic acid group, which is converted to a species that reacts readily with amines. This process provides support for the chemo-autotrophic theory5–8 for the origin of life, in which pyrite formation supplies the energy source for the first autocatalytic reproduction cycle.

Protein synthesis in aqueous environments, facilitated by sequential amino acid condensation forming peptides, is a ubiquitous process in modern biology, and a fundamental reaction necessary in prebiotic chemistry. Such reactions, however, are condensation reactions, requiring the elimination of a water molecule for every peptide bond formed, and are thus unfavorable in aqueous environments both from a thermodynamic and kinetic point of view. 1


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God's Undertaker: Has Science Buried God? Por John C. Lennox, page 127

Our amino acids have to be joined together. Functional protein requires all the bonds to be of a certain type – peptide bonds – in order for it to fold into the correct 3-dimensional structure. Yet in prebiotic simulations no more than half of the bonds are peptide bonds. So the probability of a peptide bond is about 1/2, and again the probability of getting 100 such bonds is 1 in 10^30. Thus the probability of getting 100 L-acids at random with peptide bonds is about 1 in 10^60. In all known forms of life, the chirality of the molecules and the peptide bonds are maintained by the genetic machinery. In the absence of such complex information processing molecules in the prebiotic state, variable chirality, bonding and amino acid sequence would not lead to reproducible folded states which are essential to molecular function.

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