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. 2011 Aug;73(1-2):10-22.
doi: 10.1007/s00239-011-9453-4. Epub 2011 Jul 22.

A model of proto-anti-codon RNA enzymes requiring L-amino acid homochirality

Albert Erives  1
Affiliations

A model of proto-anti-codon RNA enzymes requiring L-amino acid homochirality

Albert Erives. J Mol Evol. 2011 Aug.

Abstract

All living organisms encode the 20 natural amino acid units of polypeptides using a universal scheme of triplet nucleotide "codons". Disparate features of this codon scheme are potentially informative of early molecular evolution: (i) the absence of any codons for D-amino acids; (ii) the odd combination of alternate codon patterns for some amino acids; (iii) the confinement of synonymous positions to a codon's third nucleotide; (iv) the use of 20 specific amino acids rather than a number closer to the full coding potential of 64; and (v) the evolutionary relationship of patterns in stop codons to amino acid codons. Here I propose a model for an ancestral proto-anti-codon RNA (pacRNA) auto-aminoacylation system and show that pacRNAs would naturally manifest features of the codon table. I show that pacRNAs could implement all the steps for auto-aminoacylation: amino acid coordination, intermediate activation of the amino acid by the 5'-end of the pacRNA, and 3'-aminoacylation of the pacRNA. The anti-codon cradles of pacRNAs would have been able to recognize and coordinate only a small number of L-amino acids via hydrogen bonding. A need for proper spatial coordination would have limited the number of chargeable amino acids for all anti-codon sequences, in addition to making some anti-codon sequences unsuitable. Thus, the pacRNA model implies that the idiosyncrasies of the anti-codon table and L-amino acid homochirality co-evolved during a single evolutionary period. These results further imply that early life consisted of an aminoacylated RNA world with a richer enzymatic potential than ribonucleotides alone.

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Figures

Fig. 1
Fig. 1
proto-anti-codon RNAs. a Relevant features of the proto-anti-codon RNA (pacRNA): steric occluding ceiling made by the first base-pair of the hairpin roof (red paired bases) over an anti-codon pocket (purple unpaired bases), an acceptor stem target sequence, and the key adenosine nucleotide to be aminoacylated (faint blue) by an l-amino acid, which has its R-group side chain facing into the anti-codon surface. b and c Shown are top–down view of the bottom two nucleotides shown in a and an amino acid zwitterion, which is placed in a certain fixed orientation required for 3′-aminoacylation of the adenosine. b An l-amino acid with its R-group side chain facing into the pacRNA molecule where it can interact with the anti-codon nucleoside bases. c A d-amino acid with its R-group side chain facing away from the pacRNA molecule. The adenine:uracil base-pair (faint blue and yellow nucleotides) is located underneath the cytosine nucleotide (green base), which is linked immediately 5′ above the uracil. The Cα atom (orange) of the amino acid rises to the level of the depicted cytosine base, which in the proposed model corresponds to nucleotide N3 of an anti-codon sequence. Atoms connecting ribose C1′ to the carbonyl oxygen are not shown
Fig. 2
Fig. 2
pacRNA cradle chemistry. a–c Shown are the three steps involved in pacRNA cradle chemistry: a amino acid binding and coordination, b intermediate activation of the amino acid carboxyl group by the 5′-end of the pacRNA, and c 3′-aminoacylation. These diagrams depict the phosphate-ribose backbone of the adenosine nucleotide that will form a 3′-l-aminoacyladenylate molecule. This adenosine is base paired with U4 and initiates the nucleophilic attack (red arrow) of the carboxyl carbon of the amino acid. This carboxyl carbon is coordinated by a H-bond (thick purple dashes) with the anti-codon surface. The Cα atom (orange) of the amino acid rises to the level of the depicted cytosine base, which in the proposed model corresponds to nucleotide N3 of an anti-codon sequence
Fig. 3
Fig. 3
The anti-codon pocket 5′-CC is specific for Gly. a Side view of a cross-section of a double-stranded RNA helix (cylinder) showing all four possible nucleotide base-pairs and their complementary Watson–Crick edges. The two anti-parallel RNA strands are shown in green and purple. The hydrogen-bond donor (D) and acceptor (A) profiles of each nucleotide are positioned along a row within each tetra-nucleotide surface and occur over the axial, medial, and distal columns along the cylindrical radius. Complementary groups on either side line up when the two surfaces are swung together (green curved arrow) while keeping the helical center in a fixed position. c Skeletal diagrams of the glycine (Gly) molecule and its physiological zwitterionic form. d The axial, medial, and distal A/D atoms of the Watson–Crick edges of the di-cytosine anti-codon pocket are depicted in red for N3 and black for N2. e–g Depicted are Gly-binding configurations that are correctly oriented for charging to an adenosine-bearing molecule that is base-paired with uracil 3′ of the anti-codon sequence, 5′-N1N2N3. The donor (D) and acceptor (A) groups for Gly and the anti-codon dinucleotide are shown in green and purple, respectively. In the proposed model, an overhanging “roof” (blue shaded nucleotides), which is provided by the first base-pair in the stem duplex functions as a ceiling over the Gly-binding pocket to prevent entry by most amino acids. h Additional Gly-binding states are available which are not in position for charging but which are related to the chargeable binding ensemble by simple rotations or translations. i The next best potential ligand for this surface is alanine (Ala, fuschia), which unlike Gly, possesses a limited ensemble of binding configurations due to its additional methyl group
Fig. 4
Fig. 4
The anti-codon pockets for short-chained l-amino acids. a After Gly, the next five amino acids with the shortest side chains are shown here with their anti-codons. Correct charging of these six amino acids by these dinucleotide sequences requires a steric ceiling base-pair (blue shading) to preclude entry by longer chained amino acids. b The chargeable binding position for l-Ala. c and d The chargeable binding position for l-Pro (c) and entry binding configurations (d) related by a simple rolling movement (curved arrow) into the chargeable position. e–g The chargeable binding positions for l-Val, l-Thr, and l-Ser
Fig. 5
Fig. 5
Anti-codon pockets for l-Ser, l-Cys, l-Leu, and l-Ile. a l-Ser and l-Cys, and their pacRNA anti-codons. b and c Proposed binding/packing arrangements for l-Ser and its alternate cognate anti-codon. d Proposed binding coordination of l-Cys and its cognate anti-codon. e l-amino acids: l-Leu and l-Ile, and their pacRNA anti-codons. f and g Proposed binding/packing arrangements for l-Leu and its two pacRNA anti-codons. h Proposed binding coordination of l-Ile and its cognate anti-codon
Fig. 6
Fig. 6
Anti-codon pockets for l-amino acids with amide or acidic groups. a–e The amide-side and carbonyl groups of l-asparagine (l-Asn), aspartate (l-Asp), l-glutamine (l-Gln), and l-glutamate (l-Glu) result in exclusive chargeable binding ensembles concentrated in the outlined surfaces as shown
Fig. 7
Fig. 7
The anti-codon pockets for long-chained l-amino acids. a l-amino acids: l-Met, l-His, l-Lys, l-Phe, l-Tyr, and l-Arg are shown with their pacRNA anti-codons and occasionally their tRNA anti-codons (blue) when these differ. Acceptor (A) and donor (D) atoms are shown for all amino acids, including two different ionized forms for l-His. b Proposed binding/packing arrangement of l-Met and its cognate anti-codon. c Proposed binding coordination of l-His and its cognate anti-codon. d Proposed coordination of l-Lys and its cognate anti-codon. Various allowable binding configurations are shown. e Proposed binding/packing arrangement of l-Phe and its cognate anti-codon. f Proposed binding/packing arrangement of l-Tyr and its cognate anti-codon. g Proposed binding coordination of l-Arg with one of its cognate anti-codons. h Top-view (5′ to 3′ looking downwards) of the anti-codon surfaces for anti-l-Arg binding pockets. The A/D atoms in red at N3 coordinate the amino and carboxy termini of l-Arg, while the A/D atoms in purple coordinate the guanido group of its side-chain. i Proposed binding coordination of l-Arg and its alternate cognate anti-codon
Fig. 8
Fig. 8
Termination codons are predetermined by anti-codon stereochemistry. a–d Top–down view of anti-codon sequences matching 5′-Y1Y2A3 looking down the axis of a helical turn. These sequences have unusually large gaps (blue planar surfaces) between the D/A atoms (red letters) of the purine adenine and the D/A atoms of the pyrimidine dincleotide. Nucleotide bases stack downward into the page, and glycosidic bonds to the ribose C1′ atom are shown in purple. These anti-codons are complements of all three translational termination signals, a ochre (5′-UAA), b amber (5′-UAG), and c opal (5′-UGA); and d the codon 5′-UGG for the bulkiest amino acid, l-Tryptophan (l-Trp). e The l-Trp zwitterion with its D and A atoms is shown in an orientation that would fit into the anti-codon sequence in d if the side chain was tilted downwards into the page. f The anti-l-Gln sequence 5′-UUG is shown for comparison. This sequence has the purine guanine instead of an adenine at N3 without creating a large gap (blue planes) to the receded pyrimidine bases at N2 and N1
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