Kästner Johannes, Senn Hans Martin, Thiel Stephan, Otte Nikolaj, Thiel Walter
Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, D-45470 Mülheim an der Ruhr, Germany.
J Chem Theory Comput. 2006 Mar;2(2):452-61. doi: 10.1021/ct050252w.
We used the free-energy perturbation (FEP) method in quantum mechanics/molecular mechanics (QM/MM) calculations to compute the free-energy profile of the hydroxylation reaction in the enzyme p-hydroxybenzoate hydroxylase (PHBH). k statistics were employed to analyze the FEP sampling including estimation of the sampling error. Various approximations of the free-energy perturbation method were tested. We find that it is adequate not only to freeze the density of the QM part during the dynamics at frozen QM geometry but also to approximate this density by electrostatic-potential-fitted point charges. It is advisable to include all atoms of a QM/MM link in the perturbation. The results of QM/MM-FEP for PHBH are in good agreement with those of thermodynamic integration and umbrella sampling.
我们在量子力学/分子力学（QM/MM）计算中使用自由能微扰（FEP）方法来计算对羟基苯甲酸羟化酶（PHBH）中羟基化反应的自由能分布。采用k统计量来分析FEP抽样，包括估计抽样误差。测试了自由能微扰方法的各种近似方法。我们发现，在动力学过程中，不仅在冻结的QM几何结构下冻结QM部分的密度是足够的，而且用静电势拟合点电荷来近似该密度也是足够的。建议在微扰中包含QM/MM连接的所有原子。PHBH的QM/MM-FEP结果与热力学积分和伞形抽样的结果吻合良好。
