生命过程和化学过程的驱动力是自由能的降低。定量的理论解释和预测这些过程需要依赖于自由能变的计算。然而自由能的精确计算必须基于大量的相空间采样。这使得高级别的分子模拟方法，比如量子力学和经典力学混合（QM/MM）的动力学模拟方法，难以应用到生物大分子自由能的研究。本项目的研究是建立在本课题组前期工作的基础上，从第一性原理出发，计算分子对外界的响应性质，从而可以快速的计算分子随环境变化而发生的能量和偶极矩变化，显著的加速QM/MM动力学模拟。并且我们将发展依赖于电子结构的范德华参数计算。通过这些研究旨在发展可靠且高效的QM/MM的动力学模拟方法，提高其在相空间采样的效率和精度。并且将这些新的方法应用到酶反应的机理研究中。

The driving force in life and chemical processes is the decreasing of free energy. Quantitative explanation and prediction of these processes from theory require computations of free energy variations. However, accurate free energy calculations depend on sufficient sampling in phase space, which hinders the applications of high level simulation methods such as QM/MM to the free energy calculations for these systems. This proposal is based on our previous work on the acceleration of QM/MM simulations, which is based on the efficient calculations of molecular energies and dipole moments with alternating MM environment utilizing the response kernel from the first principle. Besides, we will also develop a QM/MM compatible van der Waals interaction model, which depends on the instantaneous electronic structure. With these progresses, we wish to build a more efficient and more reliable QM/MM simulation method, which can dramatically enhance phase space sampling. And we will apply this new QM/MM method in the study of a methyltransferase.