FoldX force field revisited, an improved version

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  • dc.contributor.author Delgado Blanco, Javier
  • dc.contributor.author Reche, Raul
  • dc.contributor.author Cianferoni, Damiano
  • dc.contributor.author Orlando, Gabriele
  • dc.contributor.author van der Kant, Rob
  • dc.contributor.author Rousseau, Frédéric
  • dc.contributor.author Schymkowitz, Joost
  • dc.contributor.author Serrano Pubull, Luis, 1982-
  • dc.date.accessioned 2025-05-14T06:01:27Z
  • dc.date.available 2025-05-14T06:01:27Z
  • dc.date.issued 2025
  • dc.description.abstract Motivation: The FoldX force field was originally validated with a database of 1000 mutants at a time when there were few high-resolution structures. Here, we have manually curated a database of 5556 mutants affecting protein stability, resulting in 2484 highly confident mutations denominated FoldX stability dataset (FSD), represented in non-redundant X-ray structures with <2.5 Å resolution, not involving duplicates, metals, or prosthetic groups. Using this database, we have created a new version of the FoldX force field by introducing pi stacking, pH dependency for all charged residues, improving aromatic-aromatic interactions, modifying the Ncap contribution and α-helix dipole, recalibrating the side-chain entropy of methionine, adjusting the H-bond parameters, and modifying the solvation contribution of tryptophan and others. Results: These changes have led to significant improvements for the prediction of specific mutants involving the above residues/interactions and a statistically significant increase of FoldX predictions, as well as for the majority of the 20 aa. Removing all training sets data from FSD [Validation FoldX Stability Dataset (VFSD) dataset] resulted in improved predictions from R = 0.693 (RMSE = 1.277 kcal/mol) to R = 0.706 (RMSE = 1.252 kcal/mol) when compared with the previously released version. FoldX achieves 95% accuracy considering an error of ±0.85 kcal/mol in prediction and an area under the curve = 0.78 for the VFSD, predicting the sign of the energy change upon mutation. Availability and implementation: FoldX versions 4.1 and 5.1 are freely available for academics at https://foldxsuite.crg.eu/.
  • dc.format.mimetype application/pdf
  • dc.identifier.citation Delgado J, Reche R, Cianferoni D, Orlando G, van der Kant R, Rousseau F, et al. FoldX force field revisited, an improved version. Bioinformatics. 2025 Feb 4;41(2):btaf064. DOI: 10.1093/bioinformatics/btaf064
  • dc.identifier.doi http://dx.doi.org/10.1093/bioinformatics/btaf064
  • dc.identifier.issn 1367-4803
  • dc.identifier.uri http://hdl.handle.net/10230/70382
  • dc.language.iso eng
  • dc.publisher Oxford University Press
  • dc.relation.ispartof Bioinformatics. 2025 Feb 4;41(2):btaf064
  • dc.rights © The Author(s) 2025. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.rights.uri http://creativecommons.org/licenses/by/4.0/
  • dc.subject.other Mutació (Biologia)
  • dc.title FoldX force field revisited, an improved version
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion

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