Xu Peng, Sattasathuchana Tosaporn, Guidez Emilie, Webb Simon P, Montgomery Kilinoelani, Yasini Hussna, Pedreira Iara F M, Gordon Mark S
Department of Chemistry, Iowa State University, Ames, Iowa 50014, USA.
Department of Chemistry, University of Colorado Denver, Denver, Colorado 80204, USA.
J Chem Phys. 2021 Mar 14;154(10):104122. doi: 10.1063/5.0040759.
A new method called QM-VM2 is presented that efficiently combines statistical mechanics with quantum mechanical (QM) energy potentials in order to calculate noncovalent binding free energies of host-guest systems. QM-VM2 efficiently couples the use of semi-empirical QM (SEQM) energies and geometry optimizations with an underlying molecular mechanics (MM) based conformational search, to find low SEQM energy minima, and allows for processing of these minima at higher levels of ab initio QM theory. A progressive geometry optimization scheme is introduced as a means to increase conformational sampling efficiency. The newly implemented QM-VM2 is used to compute the binding free energies of the host molecule cucurbit[7]uril and a set of 15 guest molecules. The results are presented along with comparisons to experimentally determined binding affinities. For the full set of 15 host-guest complexes, which have a range of formal charges from +1 to +3, SEQM-VM2 based binding free energies show poor correlation with experiment, whereas for the ten +1 complexes only, a significant correlation (R = 0.8) is achieved. SEQM-VM2 generation of conformers followed by single-point ab initio QM calculations at the dispersion corrected restricted Hartree-Fock-D3(BJ) and TPSS-D3(BJ) levels of theory, as post-processing corrections, yields a reasonable correlation with experiment for the full set of host-guest complexes (R = 0.6 and R = 0.7, respectively) and an excellent correlation for the +1 formal charge set (R = 1.0 and R = 0.9, respectively), as long as a sufficiently large basis set (triple-zeta quality) is employed. The importance of the inclusion of configurational entropy, even at the MM level, for the achievement of good correlation with experiment was demonstrated by comparing the calculated ΔE values with experiment and finding a considerably poorer correlation with experiment than for the calculated free energy ΔE - TΔS. For the complete set of host-guest systems with the range of formal charges, it was observed that the deviation of the predicted binding free energy from experiment correlates somewhat with the net charge of the systems. This observation leads to a simple empirical interpolation scheme to improve the linear regression of the full set.
提出了一种名为QM-VM2的新方法，该方法有效地将统计力学与量子力学（QM）能量势相结合，以计算主客体系统的非共价结合自由能。QM-VM2有效地将半经验QM（SEQM）能量和几何优化的使用与基于分子力学（MM）的构象搜索相结合，以找到低SEQM能量最小值，并允许在更高水平的从头算QM理论下处理这些最小值。引入了一种渐进几何优化方案，作为提高构象采样效率的一种手段。新实现的QM-VM2用于计算主体分子葫芦[7]脲与一组15个客体分子的结合自由能。给出了结果，并与实验测定的结合亲和力进行了比较。对于全套15种主客体配合物，其形式电荷范围为+1至+3，基于SEQM-VM2的结合自由能与实验的相关性较差，而仅对于10种+1配合物，实现了显著的相关性（R = 0.8）。作为后处理校正，在色散校正的受限Hartree-Fock-D3(BJ)和TPSS-D3(BJ)理论水平上进行单点从头算QM计算的SEQM-VM2构象生成，对于全套主客体配合物与实验产生了合理的相关性（分别为R = 0.6和R = 0.7），对于形式电荷为+1的集合产生了极好的相关性（分别为R = 1.0和R = 0.9），只要使用足够大的基组（三重ζ质量）。通过将计算的ΔE值与实验进行比较，并发现与计算的自由能ΔE - TΔS相比与实验的相关性明显更差，证明了即使在MM水平上包含构型熵对于实现与实验的良好相关性的重要性。对于具有形式电荷范围的全套主客体系统，观察到预测的结合自由能与实验的偏差与系统的净电荷有些相关。这一观察结果导致了一种简单的经验插值方案，以改善全套的线性回归。
