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Binding free energies for nicotine analogs inhibiting cytochrome P450 2A6 by a combined use of molecular dynamics simulations and QM/MM-PBSA calculations.

ABSTRACT: Molecular dynamics (MD) simulations and hybrid quantum mechanical/molecular mechanical (QM/MM) calculations have been performed to explore the dynamic behaviors of cytochrome P450 2A6 (CYP2A6) binding with nicotine analogs (that are typical inhibitors) and to calculate their binding free energies in combination with Poisson-Boltzmann surface area (PBSA) calculations. The combined MD simulations and QM/MM-PBSA calculations reveal that the most important structural parameters affecting the CYP2A6-inhibitor binding affinity are two crucial internuclear distances, that is, the distance between the heme iron atom of CYP2A6 and the coordinating atom of the inhibitor, and the hydrogen-bonding distance between the N297 side chain of CYP2A6 and the pyridine nitrogen of the inhibitor. The combined MD simulations and QM/MM-PBSA calculations have led to dynamic CYP2A6-inhibitor binding structures that are consistent with the observed dynamic behaviors and structural features of CYP2A6-inhibitor binding, and led to the binding free energies that are in good agreement with the experimentally-derived binding free energies. The agreement between the calculated binding free energies and the experimentally-derived binding free energies suggests that the combined MD and QM/MM-PBSA approach may be used as a valuable tool to accurately predict the CYP2A6-inhibitor binding affinities in future computational design of new, potent and selective CYP2A6 inhibitors.

SUBMITTER: Lu H

PROVIDER: S-EPMC4012391 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Binding free energies for nicotine analogs inhibiting cytochrome P450 2A6 by a combined use of molecular dynamics simulations and QM/MM-PBSA calculations.

Lu Haiting H Huang Xiaoqin X AbdulHameed Mohamed Diwan M MD Zhan Chang-Guo CG

Bioorganic & medicinal chemistry 20140303 7

Molecular dynamics (MD) simulations and hybrid quantum mechanical/molecular mechanical (QM/MM) calculations have been performed to explore the dynamic behaviors of cytochrome P450 2A6 (CYP2A6) binding with nicotine analogs (that are typical inhibitors) and to calculate their binding free energies in combination with Poisson-Boltzmann surface area (PBSA) calculations. The combined MD simulations and QM/MM-PBSA calculations reveal that the most important structural parameters affecting the CYP2A6- ...[more]

PMID: 24631364

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Project description:Recent experimental studies show that usage of perfluoro decanoic acid (PFDA), as a dummy substrate, can elicit P450BM3 to perform hydroxylation of small alkanes, such as methane (ref. 17) and propane (ref. 17 and ref. 18). To comprehend the mechanism whereby PFDA operates to potentiate P450BM3 to catalyze the hydroxylation of small alkanes, we used molecular dynamics (MD) and hybrid quantum mechanical / molecular mechanical (QM/MM) calculations. The MD results show that without the PFDA, methane escapes the active site, while the presence of PFDA can potentially induce a productive Cpd I-Methane juxtaposition for rapid oxidation. Nevertheless, when only a single methane molecule is present near the PFDA, it still escapes the pocket within less than a nanosecond. However, when three methane molecules are present in the pocket, they alternate quasi-periodically such that at all times (within 10 ns), a molecule of methane is always present in the proximity of Cpd I in a reactive conformation. Our results further demonstrate that the PFDA does not exert any electrostatic catalysis, whether the PFDA is in the protonated or deprotonated forms. Taken together, we conclude that methane hydroxylation requires, in addition to PFDA, a high partial pressure of methane that will cause a high methane concentration in the active site. Further study of ethane and propane hydroxylations demonstrates that higher alkane concentration is helpful for all the three small alkanes. Thus for the smallest alkane, methane, at least three molecules are necessary whereas for the larger ethane, two molecules are needed to force one ethane to be closer to Cpd I. Finally, for propane a second molecule is helpful but not absolutely necessary; for this molecule the PFDA may well be sufficient to keep propane close to Cpd I for efficient oxidation. We therefore propose that high alkane pressure should assist small alkane hydroxylation by P450 in a manner inversely proportional to the size of the alkanes.

Dataset Information

Binding free energies for nicotine analogs inhibiting cytochrome P450 2A6 by a combined use of molecular dynamics simulations and QM/MM-PBSA calculations.

Publications

Binding free energies for nicotine analogs inhibiting cytochrome P450 2A6 by a combined use of molecular dynamics simulations and QM/MM-PBSA calculations.

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