title: Conformational Substrate Selection Contributes to the Enzymatic Catalytic Reaction Mechanism of Pin1.
abstract: Conformational changes in enzymes and their role in their catalytic activity have been thoroughly addressed experimentally and theoretically. There is a vivid discussion in the field of enzyme catalysis on whether conformational changes of the enzyme are coupled to catalysis, or whether transition state stabilization through the preorganized protein and its electrostatic properties govern the catalysis. In this study, an additional contribution to the catalysis of one specific enzyme, Pin1, is proposed, which arises from its conformational selection of the peptide substrate from aqueous solution with the lowest activation barrier. The most stable conformers of the reactant (cis) and product (trans) peptide were identified through molecular dynamics simulations in combination with metadynamics. The cis-trans isomerization reaction was studied with quantum mechanical/molecular mechanical molecular dynamics simulations and density functional theory together with the mean reaction force, which allows us to separate structural and electronic contributions to the activation barrier. Our results show that enzyme Pin1 binds the trans isomer in the conformation of the peptide with the smallest activation barrier and reduces the barrier further through specific substrate-enzyme interactions, as we have shown previously. The activation barrier of the cis peptide is independent of the conformer and remains unchanged in the enzyme.
authors.affiliation: Departamento de Físico-Química, Facultad de Ciencias Químicas, Universidad de Concepción , 4030000 Concepción, Chile.
authors.forename: Esteban
authors.identifier: 0000-0003-1785-4558
authors.initials: E
authors.lastname: Vöhringer-Martinez
authors.affiliation: Departamento de Físico-Química, Facultad de Ciencias Químicas, Universidad de Concepción , 4030000 Concepción, Chile.
authors.forename: Ciro
authors.initials: C
authors.lastname: Dörner
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D055162:Biocatalysis; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D006801:Humans; D007536:Isomerism; D007700:Kinetics; D056004:Molecular Dynamics Simulation; D000072340:NIMA-Interacting Peptidylprolyl Isomerase / Q000737:chemistry* / Q000378:metabolism; D009842:Oligopeptides / Q000737:chemistry* / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D017433:Protein Structure, Secondary; D011789:Quantum Theory; D055672:Static Electricity; D013379:Substrate Specificity; D013816:Thermodynamics; D013912:Threonine / Q000737:chemistry / Q000378:metabolism*; D014867:Water / Q000737:chemistry
chemical_list: D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D009842:Oligopeptides; D014867:Water; D013912:Threonine; C000606846:PIN1 protein, human