Laboratory of Computational Biology, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, 20852, USA.
Department of Chemistry, University of South Florida, Tampa, Florida, 33620, USA.
J Comput Aided Mol Des. 2018 Oct;32(10):983-999. doi: 10.1007/s10822-018-0165-3. Epub 2018 Oct 1.
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 three 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 two for both standard and bonus set submissions ([Formula: see text] of 0.42 and 0.26, [Formula: see text] of 0.64 and 0.47 respectively). High RMSE and moderate correlation strongly indicated the presence of systematic error. Identifiable issues were ameliorated for two of the guest molecules, resulting in a reduction of error and pointing to strong prospects for the future use of this methodology.
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 挑战赛中，通常无法实现优于标准加和（MM）力场的改进。通常，这种方法是通过使用参考势或所谓的“间接方法”实现的，并且本质上依赖于 MM 和 QM/MM 构象空间之间存在足够的重叠。这种重叠通常很差，特别是对于使用自由能微扰在感兴趣的最终状态（例如，结合和非结合状态）执行 MM 到 QM/MM 自由能校正。然而，通过利用最能再现所需 QM 理论水平上获得的力的 MM 参数，可以减少 MM 和 QM/MM 之间的构象差异。为此，我们试图使用力匹配来为 SAMPL6 CB[8]主体-客体结合挑战生成 MM 参数，经典地计算结合自由能，并应用能量末端状态校正来获得 QM/MM 结合自由能差异。对于标准的 11 个分子集和奖励集（包括三个额外的挑战分子），误差统计数据，如均方根偏差（RMSE）相当差（5.5 和 5.4 kcal/mol）。然而，对于标准集和奖励集的提交，相关统计数据都在前两名（[公式：见文本]分别为 0.42 和 0.26，[公式：见文本]分别为 0.64 和 0.47）。高 RMSE 和中等相关性强烈表明存在系统误差。对于两个客体分子中的两个分子，可识别的问题得到了改善，从而降低了误差，并为该方法的未来应用指明了方向。
