The genetic architecture of protein stability

Mostra el registre complet Registre parcial de l'ítem

  • dc.contributor.author Faure, Andre J.
  • dc.contributor.author Martí Aranda, Aina
  • dc.contributor.author Hidalgo-Carcedo, Cristina
  • dc.contributor.author Beltran, Antoni
  • dc.contributor.author Schmiedel, Jörn M.
  • dc.contributor.author Lehner, Ben, 1978-
  • dc.date.accessioned 2024-12-02T16:19:05Z
  • dc.date.available 2024-12-02T16:19:05Z
  • dc.date.issued 2024
  • dc.description.abstract There are more ways to synthesize a 100-amino acid (aa) protein (20100) than there are atoms in the universe. Only a very small fraction of such a vast sequence space can ever be experimentally or computationally surveyed. Deep neural networks are increasingly being used to navigate high-dimensional sequence spaces1. However, these models are extremely complicated. Here, by experimentally sampling from sequence spaces larger than 1010, we show that the genetic architecture of at least some proteins is remarkably simple, allowing accurate genetic prediction in high-dimensional sequence spaces with fully interpretable energy models. These models capture the nonlinear relationships between free energies and phenotypes but otherwise consist of additive free energy changes with a small contribution from pairwise energetic couplings. These energetic couplings are sparse and associated with structural contacts and backbone proximity. Our results indicate that protein genetics is actually both rather simple and intelligible.
  • dc.description.sponsorship This work was funded by a European Research Council Advanced Grant (883742), the Spanish Ministry of Science and Innovation (LCF/PR/HR21/52410004, EMBL Partnership, Severo Ochoa Centre of Excellence), the Bettencourt Schueller Foundation, the AXA Research Fund, Agencia de Gestio d’Ajuts Universitaris i de Recerca (AGAUR, 2017 SGR 1322) and the CERCA Program/Generalitat de Catalunya. A.J.F. was funded by a Ramón y Cajal fellowship (RYC2021-033375-I) financed by the Spanish Ministry of Science and Innovation (MCIN/AEI/10.13039/501100011033) and the European Union (NextGenerationEU/PRTR). A.M.-A. was funded by a fellowship from ”laCaixa” Foundation (ID 100010434, fellowship code B006052). We thank all members of the Lehner Lab for helpful discussions and suggestions.
  • dc.format.mimetype application/pdf
  • dc.identifier.citation Faure AJ, Martí-Aranda A, Hidalgo-Carcedo C, Beltran A, Schmiedel JM, Lehner B. The genetic architecture of protein stability. Nature. 2024 Oct;634(8035):995-1003. DOI: 10.1038/s41586-024-07966-0
  • dc.identifier.doi http://dx.doi.org/10.1038/s41586-024-07966-0
  • dc.identifier.issn 0028-0836
  • dc.identifier.uri http://hdl.handle.net/10230/68884
  • dc.language.iso eng
  • dc.publisher Nature Research
  • dc.relation.ispartof Nature. 2024 Oct;634(8035):995-1003
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/883742
  • dc.rights © The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.rights.uri http://creativecommons.org/licenses/by/4.0/
  • dc.subject.keyword Biophysics
  • dc.subject.keyword Computational biology and bioinformatics
  • dc.subject.keyword Genomics
  • dc.title The genetic architecture of protein stability
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion

Col·leccions

Articles (Center for Genomic Regulation (CRG))
Documents OpenAIRE (Open Access Infrastructure for Research in Europe)