Escobedo, AlbertVoigt, GesaFaure, Andre J.Lehner, Ben, 1978-2025-09-292025-09-292025Escobedo A, Voigt G, Faure AJ, Lehner B. Genetics, energetics, and allostery in proteins with randomized cores and surfaces. Science. 2025 Jul 24;389(6758):eadq3948. DOI: 10.1126/science.adq39480036-8075http://hdl.handle.net/10230/71290A 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.application/pdfengThis is the author’s version of the work. It is posted here by permission of the AAAS for personal use, not for redistribution. The definitive version was published in Science on 2025 Jul 24;389(6758):eadq3948, DOI: 10.1126/science.adq3948Seqüència d'aminoàcidsProteïnes--Anàlisiinfo:eu-repo/semantics/articlehttp://dx.doi.org/10.1126/science.adq3948info:eu-repo/semantics/openAccess