Reduced alphabet of prebiotic amino acids optimally encodes the conformational space of diverse extant protein folds

Armando D Solis

doi:10.1186/s12862-019-1464-6

Abstract

BackgroundThere is wide agreement that only a subset of the twenty standard amino acids existed prebiotically in sufficient concentrations to form functional polypeptides. We ask how this subset, postulated as {A,D,E,G,I,L,P,S,T,V}, could have formed structures stable enough to found metabolic pathways. Inspired by alphabet reduction experiments, we undertook a computational analysis to measure the structural coding behavior of sequences simplified by reduced alphabets. We sought to discern characteristics of the prebiotic set that would endow it with unique properties relevant to structure, stability, and folding.ResultsDrawing on a large dataset of single-domain proteins, we employed an information-theoretic measure to assess how well the prebiotic amino acid set preserves fold information against all other possible ten-amino acid sets. An extensive virtual mutagenesis procedure revealed that the prebiotic set excellently preserves sequence-dependent information regarding both backbone conformation and tertiary contact matrix of proteins. We observed that information retention is fold-class dependent: the prebiotic set sufficiently encodes the structure space of α/β and α + β folds, and to a lesser extent, of all-α and all-β folds. The prebiotic set appeared insufficient to encode the small proteins. Assessing how well the prebiotic set discriminates native vs. incorrect sequence-structure matches, we found that α/β and α + β folds exhibit more pronounced energy gaps with the prebiotic set than with nearly all alternatives.ConclusionsThe prebiotic set optimally encodes local backbone structures that appear in the folded environment and near-optimally encodes the tertiary contact matrix of extant proteins. The fold-class-specific patterns observed from our structural analysis confirm the postulated timeline of fold appearance in proteogenesis derived from proteomic sequence analyses. Polypeptides arising in a prebiotic environment will likely form α/β and α + β-like folds if any at all. We infer that the progressive expansion of the alphabet allowed the increased conformational stability and functional specificity of later folds, including all-α, all-β, and small proteins. Our results suggest that prebiotic sequences are amenable to mutations that significantly lower native conformational energies and increase discrimination amidst incorrect folds. This property may have assisted the genesis of functional proto-enzymes prior to the expansion of the full amino acid alphabet.

Highlights

There is wide agreement that only a subset of the twenty standard amino acids existed prebiotically in sufficient concentrations to form functional polypeptides
We examined the performance of all alphabet reductions n-member reduced alphabet (Rn) in preserving fold information across all single domain folds, in order to explore the viability of alphabet reduction across fold space
We find that the prebiotic set is optimal in encoding the spectrum of local backbone structures that appears in the folded environment of extant proteins

Summary

Introduction

There is wide agreement that only a subset of the twenty standard amino acids existed prebiotically in sufficient concentrations to form functional polypeptides. Bolstered by analysis of meteorite composition [2], a reanalysis of diverse experiments simulating early conditions [3], structural and thermodynamic considerations [4, 5], and genomic and proteomic studies [6, 7], there is wide agreement that the amino acids {A,D, E,G,I,L,P,S,T,V} were sufficiently present as life began to form, and that the polymers of these amino acids would have composed the first functional biomolecules [8] These amino acids likely dominated the composition of polypeptides and simple proto-enzymes, whose beneficial interactions with cofactors, metals, mineral surfaces, and nucleotides may have facilitated early metabolic pathways. The hypothesis that particular folds can be formulated with a simplified amino acid alphabet is supported by experimental efforts which demonstrate that structure and function can be preserved with significant alphabet reduction [12,13,14] Among these studies are successful attempts employing the prebiotic set explicitly to reduce the sequence complexity of select target proteins [15,16,17,18]

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