<br>氨基酸字母的早期选择是根据可折叠性的生物物理限制自适应地形成的,Journal of the American Chemical Society

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氨基酸字母的早期选择是根据可折叠性的生物物理限制自适应地形成的
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2023-02-24 , DOI: 10.1021/jacs.2c12987
Mikhail Makarov ₁ , Alma C Sanchez Rocha ₁ , Robin Krystufek _{2,

3} , Ivan Cherepashuk ₁ , Volha Dzmitruk ₄ , Tatsiana Charnavets ₄ , Anneliese M Faustino ₅ , Michal Lebl ₃ , Kosuke Fujishima _{6,

7} , Stephen D Fried _{5,

8} , Klara Hlouchova _{1,

3}

Affiliation

现代蛋白质依赖于 20 种经典氨基酸 (AA) 的准通用库，而大量证据表明古代蛋白质依赖于 10 种“早期”氨基酸的有限字母表，而 10 种“晚期”氨基酸是生物合成的产物途径。然而，许多非蛋白氨基酸也可在生命前获得，这就引出了两个基本问题：为什么我们有当前的现代氨基酸字母表？如果不同的氨基酸组成遗传密码，蛋白质是否也能够折叠成球状结构？在这里，我们通过实验评估了合成组合 25 聚肽文库中几种益生元相关氨基酸的溶解度和二级结构倾向。将生命前最丰富的线性脂肪族和碱性残基与其他早期氨基酸一起掺入或代替其他早期氨基酸，以探索这些替代序列空间。结果表明，可折叠性可能是选择规范字母表的关键因素。尽管它们的益生元丰度很高，但无支链脂肪族氨基酸仍被从蛋白质字母表中清除，因为它们产生过度溶解且包装效率低的多肽。令人惊讶的是，我们发现短链碱性氨基酸的包含也会降低多肽的二级结构潜力，为此我们提出了一个生物物理模型。我们的结果支持这样的观点，即尽管缺乏基本残基，早期的规范字母表在支持蛋白质折叠方面具有显着的适应性，并解释了为什么基本残基仅在蛋白质进化的后期阶段才被纳入。

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Early Selection of the Amino Acid Alphabet Was Adaptively Shaped by Biophysical Constraints of Foldability

Whereas modern proteins rely on a quasi-universal repertoire of 20 canonical amino acids (AAs), numerous lines of evidence suggest that ancient proteins relied on a limited alphabet of 10 “early” AAs and that the 10 “late” AAs were products of biosynthetic pathways. However, many nonproteinogenic AAs were also prebiotically available, which begs two fundamental questions: Why do we have the current modern amino acid alphabet and would proteins be able to fold into globular structures as well if different amino acids comprised the genetic code? Here, we experimentally evaluate the solubility and secondary structure propensities of several prebiotically relevant amino acids in the context of synthetic combinatorial 25-mer peptide libraries. The most prebiotically abundant linear aliphatic and basic residues were incorporated along with or in place of other early amino acids to explore these alternative sequence spaces. The results show that foldability was likely a critical factor in the selection of the canonical alphabet. Unbranched aliphatic amino acids were purged from the proteinogenic alphabet despite their high prebiotic abundance because they generate polypeptides that are oversolubilized and have low packing efficiency. Surprisingly, we find that the inclusion of a short-chain basic amino acid also decreases polypeptides’ secondary structure potential, for which we suggest a biophysical model. Our results support the view that, despite lacking basic residues, the early canonical alphabet was remarkably adaptive at supporting protein folding and explain why basic residues were only incorporated at a later stage of protein evolution.

更新日期：2023-02-24

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