Departamento de Físico-Química, Facultad de Ciencias Químicas, Universidad de Concepción, 4070386 Concepción, Chile.
J Chem Inf Model. 2021 Sep 27;61(9):4462-4474. doi: 10.1021/acs.jcim.1c00655. Epub 2021 Aug 31.
Host-guest systems are widely used in benchmarks as model systems to improve computational methods for absolute binding free energy predictions. Recent advances in sampling algorithms for alchemical free energy calculations and the increase in computational power have made their binding affinity prediction primarily dependent on the quality of the force field. Here, we propose a new methodology to derive the atomic charges of host-guest systems based on quantum mechanics/molecular mechanics calculations and minimal basis iterative stockholder (MBIS) partitioning of the polarized electron density. A newly developed interface between the OpenMM and ORCA software packages provides D-MBIS charges that represent the guest's average electrostatic interactions in the hosts or the solvent. The simulation workflow also calculates the average energy required to polarize the guest in the bound and unbound state. Alchemical free energy calculations using the general Amber force field parameters with D-MBIS charges improve the binding affinity prediction of six guests bound to two octa acid hosts compared to the AM1-BCC charge set after correction with the average energetic polarization cost. This correction originates from the difference in potential energy that is required to polarize the guest in the bound and unbound state and contributes significantly to the binding affinity of anionic guests.
主体-客体系统被广泛用于基准测试中，作为模型系统来改进绝对结合自由能预测的计算方法。最近，用于计算加和自由能的采样算法的进展和计算能力的提高，使得它们的结合亲和力预测主要取决于力场的质量。在这里，我们提出了一种新的方法，基于量子力学/分子力学计算和极化电子密度的最小基迭代股东（MBIS）分区，来推导主体-客体系统的原子电荷。OpenMM 和 ORCA 软件包之间新开发的接口提供了 D-MBIS 电荷，代表了客体在主体或溶剂中的平均静电相互作用。模拟工作流程还计算了将客体极化到结合态和非结合态所需的平均能量。使用带有 D-MBIS 电荷的通用 Amber 力场参数进行加和自由能计算，可以改善六种客体与两个辛二酸主体结合的结合亲和力预测，与使用 AM1-BCC 电荷集并通过平均极化能成本校正后相比。这种校正源于将客体极化到结合态和非结合态所需的势能差异，并且对阴离子客体的结合亲和力有很大的贡献。
