Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, D-45470 Mülheim an der Ruhr, Germany.
J Chem Phys. 2013 Aug 14;139(6):064105. doi: 10.1063/1.4817402.
The dual Hamiltonian free energy perturbation (DH-FEP) method is designed for accurate and efficient evaluation of the free energy profile of chemical reactions in quantum mechanical/molecular mechanical (QM/MM) calculations. In contrast to existing QM/MM FEP variants, the QM region is not kept frozen during sampling, but all degrees of freedom except for the reaction coordinate are sampled. In the DH-FEP scheme, the sampling is done by semiempirical QM/MM molecular dynamics (MD), while the perturbation energy differences are evaluated from high-level QM/MM single-point calculations at regular intervals, skipping a pre-defined number of MD sampling steps. After validating our method using an analytic model potential with an exactly known solution, we report a QM/MM DH-FEP study of the enzymatic reaction catalyzed by chorismate mutase. We suggest guidelines for QM/MM DH-FEP calculations and default values for the required computational parameters. In the case of chorismate mutase, we apply the DH-FEP approach in combination with a single one-dimensional reaction coordinate and with a two-dimensional collective coordinate (two individual distances), with superior results for the latter choice.
双哈密顿自由能微扰（DH-FEP）方法旨在准确高效地评估QM/MM 计算中化学反应的自由能分布。与现有的 QM/MM FEP 变体不同，在采样过程中不会冻结 QM 区域，而是除反应坐标外的所有自由度都进行采样。在 DH-FEP 方案中，采样是通过半经验 QM/MM 分子动力学（MD）完成的，而扰动能量差异则是通过在规则间隔处进行高精度 QM/MM 单点计算来评估的，跳过了预定义数量的 MD 采样步骤。在用具有确切已知解的解析模型势对我们的方法进行验证后，我们报告了天冬氨酸转氨甲酰酶催化的酶反应的 QM/MM DH-FEP 研究。我们为 QM/MM DH-FEP 计算提出了指南，并为所需计算参数提供了默认值。就天冬氨酸转氨甲酰酶而言，我们将 DH-FEP 方法与单个一维反应坐标和二维集体坐标（两个单独的距离）相结合，后者的结果更优。
