Institute of Molecular Modeling and Simulation, University of Natural Resources and Life Sciences, Muthgasse 18, 1190 Vienna, Austria.
Eur Biophys J. 2012 Dec;41(12):1065-76. doi: 10.1007/s00249-012-0865-x. Epub 2012 Oct 20.
Cytochrome P450 2D6 is a major drug-metabolising enzyme with a wide substrate range. A single-point mutation introduced in this enzyme induces stereoselective binding of R and S-propranolol whereas the wild type has no preference. The system has previously been studied both experimentally and computationally (de Graaf et al. in Eur Biophys J 36:589-599, 2007a). The in silico study reported hysteresis and significant deviations from closure of thermodynamic cycles, probably because of lack of sampling. Here, we focus on the effect of prolonged simulation time and enhanced sampling methods, such as Hamiltonian replica exchange, to reduce these problems and to improve the precision of free energy calculations. Finally we rationalize the results at a molecular level and compare data with experimental findings and previously estimated free energies.
细胞色素 P450 2D6 是一种主要的药物代谢酶，具有广泛的底物范围。该酶中的单点突变会导致 R 和 S-普萘洛尔的立体选择性结合，而野生型则没有偏好。该系统之前已经进行了实验和计算研究（de Graaf 等人，Eur Biophys J 36:589-599, 2007a）。据报道，在计算机研究中存在滞后现象和热力学循环闭合的显著偏差，可能是由于采样不足所致。在这里，我们专注于延长模拟时间和增强采样方法（如哈密顿复制交换）的效果，以减少这些问题并提高自由能计算的精度。最后，我们从分子水平上对结果进行合理化，并将数据与实验结果和以前估计的自由能进行比较。
