Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, 9500 Gilman Drive, Room# 3224, La Jolla, CA 92093-0736, USA.
J Comput Aided Mol Des. 2012 May;26(5):517-25. doi: 10.1007/s10822-012-9544-3. Epub 2012 Jan 25.
We used the second-generation mining minima method (M2) to compute the binding affinities of the novel host-guest complexes in the SAMPL3 blind prediction challenge. The predictions were in poor agreement with experiment, and we conjectured that much of the error might derive from the force field, CHARMm with Vcharge charges. Repeating the calculations with other generalized force-fields led to no significant improvement, and we observed that the predicted affinities were highly sensitive to the choice of force-field. We therefore embarked on a systematic evaluation of a set of generalized force fields, based upon comparisons with PM6-DH2, a fast yet accurate semi-empirical quantum mechanics method. In particular, we compared gas-phase interaction energies and entropies for the host-guest complexes themselves, as well as for smaller chemical fragments derived from the same molecules. The mean deviations of the force field interaction energies from the quantum results were greater than 3 kcal/mol and 9 kcal/mol, for the fragments and host-guest systems respectively. We further evaluated the accuracy of force-fields for computing the vibrational entropies and found the mean errors to be greater than 4 kcal/mol. Given these errors in energy and entropy, it is not surprising in retrospect that the predicted binding affinities deviated from the experiment by several kcal/mol. These results emphasize the need for improvements in generalized force-fields and also highlight the importance of systematic evaluation of force-field parameters prior to evaluating different free-energy methods.
我们使用第二代挖掘极小值方法（M2）来计算 SAMPL3 盲测挑战中新型主体-客体配合物的结合亲和力。预测结果与实验结果相差较大，我们推测大部分误差可能来自于力场，即带有 Vcharge 电荷的 CHARMm。使用其他广义力场重复计算并没有显著改善，我们观察到预测亲和力对力场的选择非常敏感。因此，我们着手对一组广义力场进行系统评估，基于与 PM6-DH2 的比较，PM6-DH2 是一种快速而准确的半经验量子力学方法。特别是，我们比较了主体-客体配合物本身以及来自相同分子的较小化学片段的气相相互作用能和熵。对于片段和主体-客体体系，力场相互作用能与量子结果的平均偏差大于 3 kcal/mol 和 9 kcal/mol。我们进一步评估了力场计算振动熵的准确性，发现平均误差大于 4 kcal/mol。考虑到这些能量和熵的误差，预测的结合亲和力与实验值相差几个 kcal/mol也就不足为奇了。这些结果强调了改进广义力场的必要性，也突出了在评估不同自由能方法之前对力场参数进行系统评估的重要性。
