Department of Material Sciences and Process Engineering, Institute of Molecular Modeling and Simulation at BOKU- University of Natural Resources and Life Sciences , Muthgasse 18, A-1190 Vienna, Austria.
J Chem Inf Model. 2014 Jan 27;54(1):151-8. doi: 10.1021/ci4006657. Epub 2014 Jan 9.
The stereoselective binding of R- and S-propranolol to the metabolic enzyme cytochrome P450 2D6 and its mutant F483A was studied using various computational approaches. Previously reported free-energy differences from Hamiltonian replica exchange simulations, combined with thermodynamic integration, are compared to the one-step perturbation approach, combined with local-elevation enhanced sampling, and an excellent agreement between methods was obtained. Further, the free-energy differences are interpreted in terms of enthalpic and entropic contributions where it is shown that exactly compensating contributions obscure a molecular interpretation of differences in the affinity while various reduced terms allow a more detailed analysis, which agree with heuristic observations on the interactions.
使用各种计算方法研究了 R-和 S-普萘洛尔与代谢酶细胞色素 P450 2D6 及其突变体 F483A 的立体选择性结合。将以前报道的来自 Hamiltonian 复制交换模拟的自由能差异与热力学积分相结合，与一步摄动方法相结合，结合局部提升增强采样，方法之间得到了很好的一致性。此外，还根据焓和熵贡献解释了自由能差异，结果表明，精确补偿的贡献掩盖了亲和力差异的分子解释，而各种简化项则允许更详细的分析，这与对相互作用的启发式观察结果一致。
