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dc.contributor.authorJespers, Willem
dc.contributor.authorIsaksen, Geir Villy
dc.contributor.authorAndberg, Tor Arne Heim
dc.contributor.authorVasile, Silvana
dc.contributor.authorvan Veen, Amber
dc.contributor.authorÅqvist, Johan
dc.contributor.authorBrandsdal, Bjørn Olav
dc.contributor.authorGutiérrez-de-Terán, Hugo
dc.date.accessioned2020-04-06T07:39:55Z
dc.date.available2020-04-06T07:39:55Z
dc.date.issued2019-08-22
dc.description.abstractPredicting the effect of single-point mutations on protein stability or protein−ligand binding is a major challenge in computational biology. Free energy calculations constitute the most rigorous approach to this problem, though the estimation of converged values for amino acid mutations remains challenging. To overcome this limitation, we developed tailored protocols to calculate free energy shifts associated with single-point mutations. We herein describe the QresFEP protocol, which includes an extension of our recent protocols to cover all amino acids mutations, based on the latest versions of the OPLS-AA force field. QresFEP is implemented in an application programming interface framework and the graphic interface QGui, for the molecular dynamics software Q. The complete protocol is benchmarked in several model systems, optimizing a number of sampling parameters and the implementation of Zwanzig’s exponential formula and Bennet’s acceptance ratio methods. QresFEP shows an excellent performance on estimating the hydration free energies of amino acid side-chain mimics, including their charged analogues. We also examined its performance on a protein−ligand binding problem of pharmaceutical relevance, the antagonism of neuropeptide Y1 G protein-coupled receptor. Here, the calculations show very good agreement with the experimental effect of 16 mutations on the binding of antagonists BIBP3226, in line with our recent applications in this field. Finally, the characterization of 43 mutations of T4-lysozyme reveals the capacity of our protocol to assess variations of the thermal stability of proteins, achieving a similar performance to alternative free energy perturbation (FEP) approaches. In summary, QresFEP is a robust, versatile, and user-friendly computational FEP protocol to examine biochemical effects of single-point mutations with high accuracy.en_US
dc.identifier.citationJespers, Isaksen GVI, Andberg TAh, Vasile, van Veen, Åqvist J, Brandsdal BO, Gutiérrez-de-Terán. QresFEP: An Automated Protocol for Free Energy Calculations of Protein Mutations in Q . Journal of Chemical Theory and Computation. 2019;15(10):5461-5473en_US
dc.identifier.cristinIDFRIDAID 1731064
dc.identifier.doi10.1021/acs.jctc.9b00538
dc.identifier.issn1549-9618
dc.identifier.issn1549-9626
dc.identifier.urihttps://hdl.handle.net/10037/18010
dc.language.isoengen_US
dc.publisherAmerican Chemical Societyen_US
dc.relation.journalJournal of Chemical Theory and Computation
dc.relation.projectIDNorges forskningsråd: 274858en_US
dc.relation.projectIDNorges forskningsråd: 262695en_US
dc.relation.projectIDinfo:eu-repo/grantAgreement/RCN/FRINATEK/274858/Norway/Evolutionary Principles of Biocatalysts From Extreme Environments//en_US
dc.relation.projectIDinfo:eu-repo/grantAgreement/RCN/SFF/262695/Norway/Hylleraas Centre for Quantum Molecular Sciences//en_US
dc.rights.accessRightsopenAccessen_US
dc.rights.holderCopyright © 2019 American Chemical Societyen_US
dc.subjectVDP::Mathematics and natural science: 400::Chemistry: 440en_US
dc.subjectVDP::Matematikk og Naturvitenskap: 400::Kjemi: 440en_US
dc.titleQresFEP: An Automated Protocol for Free Energy Calculations of Protein Mutations in Qen_US
dc.type.versionacceptedVersionen_US
dc.typeJournal articleen_US
dc.typeTidsskriftartikkelen_US
dc.typePeer revieweden_US


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