The challenge of predicting distal active site mutations in computational enzyme design
dc.contributor.author
dc.date.accessioned
2023-07-28T10:45:17Z
dc.date.available
2023-07-28T10:45:17Z
dc.date.issued
2021-05
dc.identifier.uri
dc.description.abstract
Many computational enzyme design approaches have been developed in recent years that focus on a reduced set of key enzymatic features. Initial protocols mostly focused on the chemical steps(s) through transition state stabilization, whereas most recent approaches exploit the enzyme conformational dynamics often crucial for substrate binding, product release, and allosteric regulation. The detailed evaluation of the conformational landscape of many laboratory-evolved enzymes has revealed dramatic changes on the relative stabilities of the conformational states after mutation, favoring those conformational states key for the novel functionality. Of note is that these mutations are often located all around the enzyme structure, which contrasts with most of the computational design strategies that reduce the problem into active site alterations. Recent computational strategies have been developed that consider enzyme design as a population shift problem, that is, redistribution of the relative stabilities of the conformational states induced by mutations. These strategies focus on reconstructing the conformational landscape of the enzyme, applying correlation-based tools to elucidate the underlying allosteric network of interactions and identify potential mutation hotspots located at the active site, but most importantly at distal positions for the first time
dc.description.sponsorship
I thank the Generalitat de Catalunya for the emerging group CompBioLab (2017 SGR-1707), Spanish MINECO for project PGC2018-102192-B-I00, and the funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (ERC-2015-StG-679001)
dc.format.mimetype
application/pdf
dc.language.iso
eng
dc.publisher
Wiley
dc.relation
PGC2018-102192-B-I00
dc.relation.isformatof
Versió postprint del document publicat a: https://doi.org/10.1002/wcms.1502
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© WIRES Computational Molecular Science, 2021, vol. 11, núm. 3, p. 1502
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Articles publicats (D-Q)
dc.rights
Tots els drets reservats
dc.title
The challenge of predicting distal active site mutations in computational enzyme design
dc.type
info:eu-repo/semantics/article
dc.rights.accessRights
info:eu-repo/semantics/openAccess
dc.relation.projectID
info:eu-repo/grantAgreement/EC/H2020/679001/EU/Network models for the computational design of proficient enzymes/NetMoDEzyme
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PGC2018-102192-B-I00/ES/EVOLUCION COMPUTACIONAL DE ENZIMAS MEDIANTE LA EXPLORACION DE LA SUPERFICIE CONFORMACIONAL/
dc.type.version
info:eu-repo/semantics/acceptedVersion
dc.identifier.doi
dc.identifier.idgrec
032127
dc.contributor.funder
dc.type.peerreviewed
peer-reviewed
dc.relation.FundingProgramme
dc.relation.ProjectAcronym
dc.identifier.eissn
1759-0884