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dc.contributor.authorDe Raffele, Daria
dc.contributor.authorMartí Forés, Sergio
dc.contributor.authorMoliner, Vicent
dc.date.accessioned2019-04-16T07:27:43Z
dc.date.available2019-04-16T07:27:43Z
dc.date.issued2019
dc.identifier.citationDE RAFFELE, Daria; MARTÍ, Sergio; MOLINER, Vicent. QM/MM Theoretical Studies of a De Novo Retro-Aldolase Design. ACS Catalysis, 2019, vol. 9, no 3, p. 2482–2492ca_CA
dc.identifier.issn2155-5435
dc.identifier.urihttp://hdl.handle.net/10234/182328
dc.description.abstractThe design of innovative enzymes is a standing goal to obtain original specific catalysts to work under mild conditions of temperature and pressure. Attempts to get artificial enzymes become particularly difficult when the target is a reaction proceeding in a multistep mechanism such as the Retro-Aldol reaction. The goal of this work is to study the reaction mechanism of the most efficient de novo retro-aldolase design, the RA95.5-8F, and to understand the origin of its catalytic power. Our theoretical studies have been based on the analysis of free-energy surfaces employing hybrid QM/MM molecular dynamics simulations, with the QM subset of atoms described by semiempirical (AM1) and DFT (M06-2X) methods. The complete free-energy landscape of the reaction, generated in terms of potentials of mean force for each step, suggest that the rate-limiting step corresponds to the decomposition of an enamine intermediate into a Schiff base. This result agrees with the experimental data. Computed inverse secondary deuterium kinetic isotope effects (2° KIEs) are also in agreement with steady-state kinetic experiments. A detailed description of the reaction mechanism at the molecular level can pave the way to propose mutations that could enhance the activity of this complex multistep catalyzed process by proposing mutations that would stabilize the transition-state structures appearing along the reaction.ca_CA
dc.format.extent11 p.ca_CA
dc.language.isoengca_CA
dc.publisherAmerican Chemical Societyca_CA
dc.relation.isPartOfACS Catalysis, 2019, vol. 9, no 3ca_CA
dc.rightsCopyright © American Chemical Societyca_CA
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/*
dc.sourcehttps://pubs.acs.org/doi/full/10.1021/acscatal.8b04457ca_CA
dc.subjectcomputational biochemistryca_CA
dc.subjectde novo enzyme designca_CA
dc.subjectfree-energy surfacesca_CA
dc.subjectmolecular dynamicsca_CA
dc.subjectQM/MMca_CA
dc.subjectretro-aldolaseca_CA
dc.titleQM/MM Theoretical Studies of a de Novo Retro-Aldolase Designca_CA
dc.typeinfo:eu-repo/semantics/articleca_CA
dc.identifier.doihttp://dx.doi.org/10.1021/acscatal.8b04457
dc.relation.projectIDSpanish Ministerio de Economia y Competitividad: CTQ2015-66223-C2; FEDER funds: CTQ2015-66223-C2; Universitat Jaume I: UJI.B2017-31; Generalitat Valencianaca_CA
dc.rights.accessRightsinfo:eu-repo/semantics/restrictedAccessca_CA
dc.type.versioninfo:eu-repo/semantics/publishedVersionca_CA


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