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Prokaryotes living at extreme environmental temperatures exhibit pronounced signatures in the amino acid composition of their proteins and nucleotide compositions of their genomes reflective of adaptation to their thermal environments. However, despite significant efforts, the definitive answer of what are the genomic and proteomic compositional determinants of Optimal Growth Temperature of prokaryotic organisms remained elusive. Here the authors performed a comprehensive analysis of amino acid and nucleotide compositional signatures of thermophylic adaptation by exhaustively evaluating all combinations of amino acids and nucleotides as possible determinants of Optimal Growth Temperature for all prokaryotic organisms with fully sequences genomes.. The authors discovered that total concentration of seven amino acids in proteomes, IVYWREL, serves as a universal proteomic predictor of Optimal Growth Temperature in prokaryotes. Resolving the old-standing controversy the authors determined that the variation in nucleotide composition (increase of purine load, or A+G content with temperature) is largely a consequence of thermal adaptation of proteins. However, the frequency with which A and G nucleotides appear as nearest neighbors in genome sequences is strongly and independently correlated with Optimal Growth Temperature. as a result of codon bias in corresponding genomes. Together these results provide a complete picture of proteomic and genomic determinants of thermophilic adaptation., Comment: in press PLoS Computational Biology; revised version

The aim of this work is to elucidate how physical principles of protein design are reflected in natural sequences that evolved in response to the thermal conditions of the environment. Using an exactly solvable lattice model, we design sequences with selected thermal properties. Compositional analysis of designed model sequences and natural proteomes reveals a specific trend in amino acid compositions in response to the requirement of stability at elevated environmental temperature, i.e. the increase of fractions of hydrophobic and charged amino acid residues at the expense of polar ones. We show that this from both ends of hydrophobicity scale trend is due to positive (to stabilize the native state) and negative (to destabilize misfolded states) components of protein design. Negative design strengthens specific repulsive nonnative interactions that appear in misfolded structures. A pressure to preserve specific repulsive interactions in non-native conformations may result in correlated mutations between amino acids which are far apart in the native state but may be in contact in misfolded conformations. Such correlated mutations are indeed found in TIM barrel and other proteins., Comment: PLoS Computational Biology, in press

In this work, we discovered a fundamental connection between selection for protein stability and emergence of preferred structures of proteins. Using standard exact 3-dimensional lattice model we evolve sequences starting from random ones and determining exact native structure after each mutation. Acceptance of mutations is biased to select for stable proteins. We found that certain structures, wonderfold, are independently discovered numerous times as native states of stable proteins in many unrelated runs of selection. Diversity of sequences that fold into wonderfold structures gives rise to superfamilies, i.e. sets of dissimilar sequences that fold into the same or very similar structures. Wonderfolds appear to be the most designable structures out of complete set of compact lattice proteins. Furthermore, proteins having wondefolds as their native structure tend to be most thermostable among all evolved proteins. This effect is purely due to the favorable geometric properties of wonderfolds and, thus, dominates any dependence on sequences. The present work establishes a model of prebiotic structure selection, which identifies dominant structural patterns emerging upon optimization of proteins for survival in hot environment. Convergently discovered prebiotic initial superfamilies with wonderfold structures could have served as a seed for subsequent biological evolution involving gene duplications and divergence.

We report here a new entropic mechanism of protein thermostability due to residual dynamics of rotamer isomerization in native state. All-atom simulations show that Lysines have much greater number of accessible rotamers than Arginines in folded states of proteins. This finding suggests that Lysines would preferentially entropically stabilize the native state. Indeed we show in computational experiments that Arginine-to-Lysine amino acid substitutions result in noticeable stabilization of proteins. We then hypothesize that if evolution uses this physical mechanisms in its strategies of thermophilic adaptation then hyperthermostable organisms would have much greater content of Lysines in their proteomes than of comparable in size and similarly charged Arginines.. Consistent with that, high-throughput comparative analysis of complete proteomes shows extremely strong bias towards Arginine-to-Lysine replacement in hyperthermophilic organisms and overall much greater content of Lysines than Arginines in hyperthermophiles. This finding cannot be explained by GC compositional biases. Our study provides an example of how analysis of a delicate physical mechanism of thermostability helps to resolve a puzzle in comparative genomics as to why aminoacid compositions of hyperthermophilic proteomes are significantly biased towards Lysines but not Arginines

In this work we employ various methods of analysis (unfolding simulations and comparative analysis of structures and sequences of proteomes of thermophilic organisms) to show that organisms can follow two major strategies of thermophilic adaptation: (i) General, non-specific, structure-based, when proteomes of certain thermophilic organisms show significant structural bias toward proteins of higher compactness. In this case thermostability is achieved by greater overall number of stabilizing contacts, none of which may be especially strong, and (ii) Specific, sequence-based, whereby sequence variations aimed at strengthening specific types of interactions (e.g. electrostatics) are applied without significantly changing structures of proteins. The choice of a certain strategy is a direct consequence of evolutionary history and environmental conditions of particular (hyper) thermophilic species: ancient hyperthermophilic organisms that directly evolved in hot environment, pursued mostly structure-based strategy, while later evolved organisms whose thermophilic adaptation was a consequence of their recolonization of hot environment, pursued specific, sequence-based strategy of thermophilic adaptation., Comment: 41 pages, 4 figures, 3 tables. Submitted