Predicting Relative Binding Affinity Using Nonequilibrium QM/MM Simulations.
Predicting Relative Binding Affinity Using Nonequilibrium QM/MM Simulations.
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DOI：
10.1021/acs.jctc.8b00685
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发表时间：
2018-10
影响因子：
5.5
通讯作者：
Meiting Wang;Y. Mei;U. Ryde
中科院分区：
文献类型：
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作者：
Meiting Wang;Y. Mei;U. Ryde
用量子力学(QM)方法计算结合自由能是出了名的费时。在这项工作中，我们研究了是否可以通过使用Jarzynski方程的非平衡(NE)分子动力学模拟来加速这种计算。我们从SAMPL4挑战出发，用参考电位法研究了9个环羧酸配体与八酸深腔宿主的结合。首先在自由能微扰的分子力学(MM)水平上，采用约束静电势荷的广义Amber力场计算了主体和配体的结合自由能。然后，通过对许多短的NE分子动力学模拟的平均，估计了从MM哈密顿量到QM/MM混合哈密顿量的自由能修正。在QM/MM计算中，配体在半经验PM6-DH+水平上被描述。结果表明，在统计不确定度范围内，该方法得到的MM→QM/MM自由能修正与其他方法的结果一致。通过运行适当数量的独立NE模拟可以获得所需的精度。对于本工作所研究的体系，对于大多数配体来说，总模拟长度为20ps是合适的，为了达到0.3kJ/mol的精度，需要36-324个模拟。
Calculating binding free energies with quantum-mechanical (QM) methods is notoriously time-consuming. In this work, we studied whether such calculations can be accelerated by using nonequilibrium (NE) molecular dynamics simulations employing Jarzynski's equality. We studied the binding of nine cyclic carboxylate ligands to the octa-acid deep-cavity host from the SAMPL4 challenge with the reference potential approach. The binding free energies were first calculated at the molecular mechanics (MM) level with free energy perturbation using the generalized Amber force field with restrained electrostatic potential charges for the host and the ligands. Then the free energy corrections for going from the MM Hamiltonian to a hybrid QM/MM Hamiltonian were estimated by averaging over many short NE molecular dynamics simulations. In the QM/MM calculations, the ligand was described at the semiempirical PM6-DH+ level. We show that this approach yields MM → QM/MM free energy corrections that agree with those from other approaches within statistical uncertainties. The desired precision can be obtained by running a proper number of independent NE simulations. For the systems studied in this work, a total simulation length of 20 ps was appropriate for most of the ligands, and 36-324 simulations were necessary in order to reach a precision of 0.3 kJ/mol.