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dc.contributor.authorRoca Moliner, María Teresa
dc.contributor.authorMoliner, Vicent
dc.contributor.authorTuñón, Iñaki
dc.identifier.citationROCA, Maite; MOLINER, Vicent; TUÑÓN, Iñaki. On the origin of Enzymatic Kinetic Isotope Effects in Human Purine Nucleoside Phosphorylase. ACS Catalysis, 2017, vol. 8, no 2, p. 815–827ca_CA
dc.description.abstractHere we report a study of the effect of heavy isotope labeling on the reaction catalyzed by human purine nucleoside phosphorylase (hPNP) to elucidate the origin of its catalytic effect and of the enzymatic kinetic isotope effect (EKIE). Using quantum mechanical and molecular mechanical (QM/MM) molecular dynamics (MD) simulations, we study the mechanism of the hPNP enzyme and the dynamic effects by means of the calculation of the recrossing transmission coefficient. A free energy surface (FES), as a function of both a chemical and an environmental coordinate, is obtained to show the role of the environment on the chemical reaction. Analysis of reactive and nonreactive trajectories allows us to study the geometric, dynamic, and electronic changes of the chemical system. Special attention is paid to the electrostatic potential created by the environment on those atoms involved in the chemical reaction. Some amino acid residues and solvent molecules that interact with the chemical system provide a specific configuration that electrostatically favor the reaction progress, producing a reactive trajectory. The EKIE is calculated within the framework of the variational transition state theory (VTST), giving very good agreement with the experimental data. According to our simulations the chemical reaction is slightly slower in the heavy enzyme than in its light counterpart enzyme because protein motions coupled to the reaction coordinate are slower. Thus, protein dynamics have a small but measurable effect on the chemical reaction rate.ca_CA
dc.format.extent13 p.ca_CA
dc.publisherAmerican Chemical Societyca_CA
dc.relation.isPartOfACS Catalysis, 2017, voil. 8, no 2ca_CA
dc.rightsCopyright © American Chemical Societyca_CA
dc.subjectenzymatic kinetic isotope effectca_CA
dc.subjectenzyme catalysisca_CA
dc.subjectprotein motionsca_CA
dc.subjectQM/MM methodsca_CA
dc.subjectvariational transition state theoryca_CA
dc.titleOrigin of Enzymatic Kinetic Isotope Effects in Human Purine Nucleoside Phosphorylaseca_CA
dc.relation.projectIDSpanish Ministerio de Economia y Competitividad-FEDER: CTQ2015-66223-C2; Generalitat Valenciana: PrometeoII/2014/022, GV/2012/053; Universitat de Valencia; UV-INV-AE11-40931; Universitat Jaume I; P1 1B2014-26, UJI-B2016-28; Ministerio de Economia y Competitividad: RYC-2014-16592ca_CA
dc.contributor.funderThe authors acknowledge the computational facilities of Universitat Jaume I and Universitat de Valencia (Tirant Supercomputer).ca_CA

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