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On the Possible Origin of Protein Homochirality, Structure, and Biochemical Function

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On the Possible Origin of Protein Homochirality, Structure, and Biochemical Function On the possible origin of protein homochirality, structure, and biochemical function Jeffrey Skolnicka,1, Hongyi Zhoua, and Mu Gaoa aCenter for the Study of Systems Biology, School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA 30332 Edited by Eugene V. Koonin, National Institutes of Health, Bethesda, MD, and approved November 13, 2019 (received for review May 13, 2019) Living systems have chiral molecules, e.g., native proteins that both (19). More recent studies suggest that aminonitriles, amino almost entirely contain L-amino acids. How protein homochirality acid precursors, readily form peptides in water, providing another emerged from a background of equal numbers of L and D amino source of non–RNA-based proteins (20). Whatever their origin, acids is among many questions about life’s origin. The origin of the minimal conjecture that protein sequences containing equal homochirality and its implications are explored in computer simu- amounts of D and L amino acids, termed demi-chiral proteins, lations examining the stability and structural and functional prop- were present in the prebiotic “soup” is the starting point of the erties of an artificial library of compact proteins containing 1:1 present analysis, which explores the stability and structural and (termed demi-chiral), 3:1, and 1:3 ratios of D:L and purely L or D functional properties of demi-chiral model proteins, 3:1 mixtures amino acids generated without functional selection. Demi-chiral of D:L and L:D amino acids and homochiral D and L proteins. proteins have shorter secondary structures and fewer internal hy- drogen bonds and are less stable than homochiral proteins. Selec- Key Questions About Demi-Chiral Proteins tion for hydrogen bonding yields a preponderance of L or D amino At first glance, one might imagine that the stability and structural acids. Demi-chiral proteins have native global folds, including sim- and functional properties of demi-chiral proteins are strikingly ilarity to early ribosomal proteins, similar small molecule ligand different from contemporary homochiral, L-amino acid proteins. binding pocket geometries, and many constellations of L-chiral Since regular secondary structures form from homochiral se- amino acids with a 1.0-Å RMSD to native enzyme active sites. quences of amino acids, in demi-chiral proteins, one might For a representative subset containing 550 active site geometries expect that the average length of regular secondary structure matching 457 (2) 4-digit (3-digit) enzyme classification (E.C.) num- elements formed by helical stretches of the same chirality might bers, native active site amino acids were generated at random for be shorter. What effect does this have on the ability of demi- BIOPHYSICS AND COMPUTATIONAL BIOLOGY 472 of 550 cases. This increases to 548 of 550 cases when similar chiral proteins to form internal hydrogen bonds? Are demi-chiral residues are allowed. The most frequently generated sequences proteins inherently less stable than chiral ones because they correspond to ancient enzymatic functions, e.g., glycolysis, repli- contain fewer internal hydrogen bonds? Are the folds of demi- cation, and nucleotide biosynthesis. Surprisingly, even without chiral proteins different from present ones (21)? For native selection, demi-chiral proteins possess the requisite marginal bio- proteins, the library of solved compact single domain native chemical function and structure of modern proteins, but were proteins has been shown to be essentially complete, viz. every thermodynamically less stable. If demi-chiral proteins were pre- native protein structure has statistically significant structural sent, they could engage in early metabolism, which created the similarity (22–24) to members of a library of randomly gener- feedback loop for transcription and cell formation. ated, artificial compact protein structures (25, 26). But what happens when the lengths of regular secondary structural ele- origin of protein chirality | origin of life | early metabolism | metabolism ments are shorter? Are their global folds different? This would first world | emergence of chiral proteins imply a discontinuous structural transition from demi-chiral to ne striking feature of biological macromolecules is that they Significance Oare chiral; for example, proteins mainly contain L-amino acids (1). One of the mysteries of the origin of life is how chiral Living systems contain mainly chiral macromolecules, including systems emerged from a background of equal amounts of D proteins. How L-chiral proteins emerged from demi-chiral – and L amino acids (2 5). The RNA world hypothesis conjectures mixtures is unknown. Our simulations show that, compared that RNA came first. These chiral molecules stored genetic to contemporary proteins, demi-chiral proteins have shorter – information and catalyzed chemical reactions (6 10). Alterna- regular secondary structures due to fewer internal hydrogen tively, in a minority view, Dyson conjectured that early, probably bonds, but similar global folds and small molecule binding sites. protein, molecules evolved at least part of the necessary chem- Demi-chiral proteins contain L-chiral substructures matching na- istry of life, viz. metabolism, before transcription emerged (11). tive active site geometries. Among the most frequently generated However, in both views—replication first or metabolism first— enzymes with native active site residues are ancient functions the question remains: how was symmetry broken to yield chiral associated with metabolism and replication. This suggests that systems? Turning to proteins, there is evidence that carbonaceous demi-chiral proteins could engage in early metabolism, creating meteorites contain an excess of L over D amino acids, with the the feedback loop for transcription and cell formation partly re- relative preference depending on meteorite origin (12–15). This sponsible for life’semergence. could partly explain proteins’ L-chirality, assuming that proteins could be made from short polypeptides. To address this issue, Dill Author contributions: J.S. designed research; J.S., H.Z., and M.G. performed research; J.S., and coworkers recently proposed the foldamer hypothesis whereby H.Z., and M.G. analyzed data; and J.S., H.Z., and M.G. wrote the paper. short hydrophobic protein chains collapse to compact structures, The authors declare no competing interest. which then catalyze the formation of longer proteins from shorter This article is a PNAS Direct Submission. ones. This view differs from Lupas (16, 17), who proposed that Published under the PNAS license. ancient proteins folded by fusion and recombination from ancestral 1To whom correspondence may be addressed. Email: [email protected]. peptides resulting from RNA-dependent translationandcatalysis This article contains supporting information online at https://www.pnas.org/lookup/suppl/ (18). Alternatively, using the “molecules in mutualism hypothesis,” doi:10.1073/pnas.1908241116/-/DCSupplemental. nucleotides and amino acids might have catalyzed the synthesis of First published December 10, 2019. www.pnas.org/cgi/doi/10.1073/pnas.1908241116 PNAS | December 26, 2019 | vol. 116 | no. 52 | 26571–26579 Downloaded by guest on September 24, 2021 chiral proteins. How different are the geometries and shapes of found active sites from independently generated sequences with their small molecule ligand binding pockets from those in homo- the correct active site L-residues correlate with ancient enzy- chiral proteins (27, 28)? If they were very dissimilar, then the matic functions. Finally, we discuss the possible ramifications of fundamental chemistry of such putative early, prebiotic proteins our results for the origin of the biochemistry of life. could have been very different from now. At the least, this would have profound implications for the validity of the Dyson model Hydrogen Bonding and Secondary Structure in Demi-Chiral that metabolism came first: metabolism and small molecule-based Proteins intermolecular signaling would have to be dramatically modified As indicated in Fig. 1, hydrogen bonding in regular secondary as the transition to chiral systems occurred. Conversely, if they are structural elements cannot occur between L and D amino acids. similar, then their chemistry could be related, providing circum- Fig. 2A clearly shows that the average hydrogen bond energy in stantial support for the metabolism-first hypothesis. the artificial polyleucine demi-chiral proteins is dramatically less We next turn to the key question of whether demi-chiral pro- than in the more chiral ones. Fig. 2B plots the fraction of pro- teins could catalyze chiral reactions. At first glance, one might say teins with greater than the fraction of hydrogen-bonded residues no; after all, the system is globally demi-chiral with, on average, on the abscissa. For demi-chiral proteins, only half have >30% of equal numbers of D and L amino acids, so how can it do chiral their residues hydrogen-bonded. In contrast, in pure D or L pro- chemistry? On deeper analysis, in a 1:1 mixture of L and D amino teins (with the same results as expected by symmetry), 60% of acids, one could, by chance, have a constellation of L amino acids their residues have internal hydrogen bonds, while 3D:L or D:3L at precisely the correct spots in the protein sequence to recapit- proteins have ∼45% of their residues with intraprotein hydrogen ulate both native active site geometry and chirality, thereby bonds. Thus, independent of the particular
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