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dc.contributor.authorArafet Cruz, Kemel
dc.contributor.authorŚwiderek, Katarzyna
dc.contributor.authorMoliner, Vicent
dc.date.accessioned2019-03-22T08:34:57Z
dc.date.available2019-03-22T08:34:57Z
dc.date.issued2018
dc.identifier.citationARAFET, Kemel; ŚWIDEREK, Katarzyna; MOLINER, Vicent. Computational Study of the Michaelis Complex Formation and the Effect on the Reaction Mechanism of Cruzain Cysteine Protease. ACS Omega, 2018, vol. 3, no 12, p. 18613-18622ca_CA
dc.identifier.issn2470-1343
dc.identifier.urihttp://hdl.handle.net/10234/181927
dc.description.abstractCruzain, a cysteine protease of the papain family, is essential in the development of the protozoan Trypanosoma cruzi, the etiologic agent of Chagas disease, making it an attractive target for developing new drugs. The present paper is aimed at the study of the catalytic mechanism of the cruzain by first exploring the different protonation states of the active site Cys25 and His159 in the Michaelis complex and the effect on the full catalytic mechanism of this enzyme. The exploration of the equilibrium between these two states has been performed with alchemical free energy perturbation methods with molecular mechanics (MM) force fields and by generating the free energy surfaces in terms of the potential of mean force computed at two levels of theory: AM1d/MM and M06-2X/6-31+G(d,p):AM1d/MM. Alternative mechanisms for the acylation step have been identified on the free energy surfaces and the results suggest the existence of three new reaction mechanisms starting from the peptide binding to the apoenzyme in its neutral Cys25S/His159 dyad state. The mechanism starting with the protonation of the nitrogen atom of the peptide followed by the attack of Cys25S– was revealed as the most favorable one, but it can be competitive with its counterpart mechanism initiated in the Cys25S–/His159H+ ion pair Michaelis complex. Analysis of energetic and average geometries will allow continuing improvement of our knowledge on this enzyme at the molecular level, which can be crucial to the design of new inhibitors based on the structures of the transition states (transition states analogues) or stable intermediates.ca_CA
dc.format.extent10 p.ca_CA
dc.format.mimetypeapplication/pdfca_CA
dc.language.isoengca_CA
dc.publisherAmerican Chemical Societyca_CA
dc.relation.isPartOfACS Omega, 2018, vol. 3, no 12ca_CA
dc.rights.urihttp://rightsstatements.org/vocab/CNE/1.0/*
dc.subjectbiochemistryca_CA
dc.subjectenzyme kineticsca_CA
dc.subjectfree energyca_CA
dc.subjectmolecular dynamicsca_CA
dc.subjectmolecular dynamics simulationca_CA
dc.subjectmolecular mechanicsca_CA
dc.subjectpotential energyca_CA
dc.subjectproteinsca_CA
dc.subjectreaction mechanismca_CA
dc.titleComputational Study of the Michaelis Complex Formation and the Effect on the Reaction Mechanism of Cruzain Cysteine Proteaseca_CA
dc.typeinfo:eu-repo/semantics/articleca_CA
dc.identifier.doihttp://dx.doi.org/10.1021/acsomega.8b03010
dc.relation.projectIDSpanish Ministerio de Economia y Competitividad: CTQ2015-66223-C2; FEDER funds: CTQ2015-66223-C2; Universitat Jaume I: UJI.B2017-31; Spanish Ministerio de Economia y Competitividad for a Juan de la Cierva -Incorporacion: IJCI-2016-27503ca_CA
dc.rights.accessRightsinfo:eu-repo/semantics/openAccessca_CA
dc.relation.publisherVersionhttps://pubs.acs.org/doi/abs/10.1021/acsomega.8b03010ca_CA
dc.type.versioninfo:eu-repo/semantics/publishedVersionca_CA


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