Force matching as a stepping stone to QM/MM CB[8] host/guest binding free energies: a SAMPL6 cautionary tale.
Force matching as a stepping stone to QM/MM CB[8] host/guest binding free energies: a SAMPL6 cautionary tale.
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DOI：
10.1007/s10822-018-0165-3
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发表时间：
2018-10
影响因子：
3.5
通讯作者：
Brooks BR
中科院分区：
文献类型：
--
作者：
Hudson PS;Han K;Woodcock HL;Brooks BR
在结合自由能计算中使用量子力学/分子力学（QM/MM）方法，特别是在SAMPL挑战中，通常不能实现对标准加性（MM）力场的改进。通常，实施是通过使用参考电位，或所谓的“间接方法”，并固有地依赖于MM和QM/MM构型空间之间存在的足够的重叠。这种重叠通常很差，特别是对于使用自由能扰动来在感兴趣的端态（例如，绑定和未绑定状态）。然而，通过利用最佳再现在所需QM理论水平下获得的力的MM参数，可以减少MM和QM/MM之间的构型差异。为此，我们试图使用力匹配来生成用于SAMPL6 CB [8]主客体结合挑战的MM参数，经典地计算结合自由能，并应用能量终态校正以获得QM/MM结合自由能差。对于11个分子的标准组和奖励组（包括3个额外的挑战分子），误差统计，如均方根偏差（RMSE）是中等差（5.5和5.4千卡/摩尔）。然而，相关性统计数据在标准和奖励集提交中均位于前2位（R2分别为0.42和0.26，τ分别为0.64和0.47）。高的RMSE和中等的相关性强烈表明存在系统误差。可识别的问题，改善了2的客体分子，从而减少了错误，并指出了未来使用这种方法的强大前景。
Use of Quantum Mechanical/Molecular Mechanical (QM/MM) methods in binding free energy calculations, particularly in the SAMPL challenge, often fail to achieve improvement over standard additive (MM) force fields. Frequently, the implementation is through use of reference potentials, or the so-called “indirect approach”, and inherently relies on sufficient overlap existing between MM and QM/MM configurational spaces. This overlap is generally poor, particularly for the use of free energy perturbation to perform the MM to QM/MM free energy correction at the end states of interest (e.g., bound and unbound states). However, by utilizing MM parameters that best reproduce forces obtained at the desired QM level of theory, it is possible to lessen the configurational disparity between MM and QM/MM. To this end, we sought to use force matching to generate MM parameters for the SAMPL6 CB[8] host-guest binding challenge, classically compute binding free energies, and apply energetic end state corrections to obtain QM/MM binding free energy differences. For the standard set of 11 molecules and the bonus set (including 3 additional challenge molecules), error statistics, such as the root mean square deviation (RMSE) were moderately poor (5.5 and 5.4 kcal/mol). Correlation statistics, however, were in the top 2 for both standard and bonus set submissions (R2 of 0.42 and 0.26, τ of 0.64 and 0.47 respectively). High RMSE and moderate correlation strongly indicated the presence of systematic error. Identifiable issues were ameliorated for 2 of the guest molecules, resulting in a reduction of error and pointing to strong prospects for future use of this methodology.
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影响因子：
4.1
作者：
BENNETT, CH
通讯作者：
BENNETT, CH
影响因子：
2.8
作者：
BEUTLER, TC;MARK, AE;VANGUNSTEREN, WF
通讯作者：
VANGUNSTEREN, WF
影响因子：
1.7
作者：
Boresch, Stefan;Woodcock, H. Lee
通讯作者：
Woodcock, H. Lee
影响因子：
4.4
作者：
BECKE, AD
通讯作者：
BECKE, AD
影响因子：
4.3
作者：
Eastman P;Swails J;Chodera JD;McGibbon RT;Zhao Y;Beauchamp KA;Wang LP;Simmonett AC;Harrigan MP;Stern CD;Wiewiora RP;Brooks BR;Pande VS
通讯作者：
Pande VS