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QM/MM modeling of the hydroxylation of the androstenedione substrate catalyzed by cytochrome P450 aromatase (CYP19A1)
dc.contributor.author | Viciano Gonzalo, Ignacio | |
dc.contributor.author | Castillo, Raquel | |
dc.contributor.author | Martí Forés, Sergio | |
dc.date.accessioned | 2016-06-02T11:45:41Z | |
dc.date.available | 2016-06-02T11:45:41Z | |
dc.date.issued | 2015-09 | |
dc.identifier.citation | Viciano, Ignacio, Raquel Castillo, and Sergio Martí. "QM/MM modeling of the hydroxylation of the androstenedione substrate catalyzed by cytochrome P450 aromatase (CYP19A1)." Journal of computational chemistry 36.23 (2015): 1736-1747. | ca_CA |
dc.identifier.uri | http://hdl.handle.net/10234/160271 | |
dc.description.abstract | CYP19A1 aromatase is a member of the Cytochrome P450 family of hemeproteins, and is the enzyme responsible for the final step of the androgens conversion into the corresponding estrogens, via a three-step oxidative process. For this reason, the inhibition of this enzyme plays an important role in the treatment of hormone-dependent breast cancer. The first catalytic subcycle, corresponding to the hydroxilation of androstenedione, has been proposed to occur through a first hydrogen abstraction and a subsequent oxygen rebound step. In present work, we have studied the mechanism of the first catalytic subcycle by means of hybrid quantum mechanics/molecular mechanics methods. The inclusion of the protein flexibility has been achieved by means of Free Energy Perturbation techniques, giving rise to a free energy of activation for the hydrogen abstraction step of 13.5 kcal/mol. The subsequent oxygen rebound step, characterized by a small free energy barrier (1.5 kcal/mol), leads to the hydroxylated products through a highly exergonic reaction. In addition, an analysis of the primary deuterium kinetic isotopic effects, calculated for the hydrogen abstraction step, reveals values (∼10) overpassing the semiclassical limit for the C[BOND]H, indicating the presence of a substantial tunnel effect. Finally, a decomposition analysis of the interaction energy for the substrate and cofactor in the active site is also discussed. According to our results, the role of the enzymatic environment consists of a transition state stabilization by means of dispersive and polarization effects. | ca_CA |
dc.description.sponsorShip | We acknowledge the Servei d'Informàtica of the Universitat Jaume I, GENCI-CINES, and BSC-Marenostrum for providing us with computer capabilities. The authors thank V. Moliner for valuable comments and discussion. | ca_CA |
dc.format.extent | 11 p. | ca_CA |
dc.format.mimetype | application/pdf | ca_CA |
dc.language.iso | eng | ca_CA |
dc.publisher | Wiley | ca_CA |
dc.relation.isPartOf | Journal of computational chemistry Volume 36, Issue 23 September 5, 2015 | ca_CA |
dc.rights | © 2015 Wiley Periodicals, Inc. | ca_CA |
dc.rights.uri | http://rightsstatements.org/vocab/InC/1.0/ | * |
dc.subject | cytochrome P450 | ca_CA |
dc.subject | compound I | ca_CA |
dc.subject | aromatase | ca_CA |
dc.subject | hydrogen abstraction | ca_CA |
dc.subject | androstenedione | ca_CA |
dc.subject | CYP19A1 | ca_CA |
dc.subject | quantum mechanics/molecular mechanics | ca_CA |
dc.title | QM/MM modeling of the hydroxylation of the androstenedione substrate catalyzed by cytochrome P450 aromatase (CYP19A1) | ca_CA |
dc.type | info:eu-repo/semantics/article | ca_CA |
dc.identifier.doi | http://dx.doi.org/10.1002/jcc.23967 | |
dc.rights.accessRights | info:eu-repo/semantics/openAccess | ca_CA |
dc.relation.publisherVersion | http://onlinelibrary.wiley.com/doi/10.1002/jcc.23967/full | ca_CA |
dc.type.version | info:eu-repo/semantics/acceptedVersion | ca_CA |
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