Centre for Computational Chemistry, School of Chemistry, University of Bristol, Cantock's Close, Bristol BS8 1TS, United Kingdom.
J Phys Chem B. 2010 Jan 21;114(2):1156-62. doi: 10.1021/jp910127j.
Prediction of the chemoselectivity of drug oxidation by the human cytochrome P450 enzymes will aid in the avoidance of adverse drug reactions. The chemoselectivity of alkene oxidation is an important problem to address, as it can result in the formation of epoxides, which can have toxic effects. In this paper the epoxidation and hydroxylation of cyclohexene and propene by the bacterial P450(cam) isoform are modeled with hybrid quantum mechanical/molecular mechanical (QM/MM) methods. Snapshots for QM/MM modeling are chosen from molecular dynamics trajectories, to sample the different conformations of the enzyme-substrate complex. The energy barriers obtained for these processes are in qualitative agreement with experimental work, supporting the use of QM/MM methods in the study of selectivity for this class of enzyme. This work highlights the complexity involved in modeling these systems with QM/MM and the importance in the selection of starting geometries.
预测人细胞色素 P450 酶对药物氧化的化学选择性将有助于避免药物不良反应。烯烃氧化的化学选择性是一个需要解决的重要问题，因为它可能导致环氧化物的形成，而环氧化物可能具有毒性作用。本文使用混合量子力学/分子力学 (QM/MM) 方法对细菌 P450(cam)同工酶中环己烯和丙烯的环氧化和羟化作用进行了建模。从分子动力学轨迹中选择 QM/MM 建模的快照，以采样酶-底物复合物的不同构象。这些过程的能量势垒与实验工作定性一致，支持在研究此类酶的选择性时使用 QM/MM 方法。这项工作强调了使用 QM/MM 对这些系统进行建模的复杂性，以及选择起始几何形状的重要性。
