Genetics, energetics, and allostery in proteins with randomized cores and surfaces

• 成果类型: Article
• 署名作者: Escobedo, Albert; Voigt, Gesa; Faure, Andre J.; Lehner, Ben
• 署名单位: Barcelona Institute of Science & Technology; Pompeu Fabra University; Centre de Regulacio Genomica (CRG); Wellcome Trust Sanger Institute; Pompeu Fabra University; ICREA
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-12775
• DOI: 10.1126/science.adq3948
• 发表日期: 2025-07-24
• 关键词: cavity-creating mutations; side-chain packing; chymotrypsin inhibitor-2; hydrophobic core; sh3 domain; thermodynamic characterization; folding kinetics; transition-state; STABILITY; fyn

摘要

A lack of systematic experimental data limits our understanding of protein evolution. In this study, we experimentally characterized proteins with randomized sequences. Vast numbers of amino acid combinations constitute stable protein cores and surfaces. However, alternative cores frequently disrupt protein function by indirect allosteric effects. Both protein stability and binding can be predicted using simple additive energy models with a small contribution from pairwise energetic couplings. Indeed, energy models trained on one protein can predict functional cores and surfaces across more than a billion years of evolution, with only rare energetic couplings that we experimentally identify limiting the transplantation of cores between highly diverged proteins. Our results reveal the simple energetic architecture of proteins and suggest that allostery is an important constraint on sequence evolution.