Shenzhen Jingtai Technology Co., Ltd. (XtalPi), Floor 3, Sf Industrial Plant, No. 2 Hongliu Road, Fubao Community, Fubao Street, Futian District, Shenzhen 518045, China.
Medicine Design, Pfizer Inc., 1 Portland Street, Cambridge, Massachusetts 02139, United States.
J Chem Theory Comput. 2024 Jan 23;20(2):799-818. doi: 10.1021/acs.jctc.3c00920. Epub 2023 Dec 29.
Biomolecular simulations have become an essential tool in contemporary drug discovery, and molecular mechanics force fields (FFs) constitute its cornerstone. Developing a high quality and broad coverage general FF is a significant undertaking that requires substantial expert knowledge and computing resources, which is beyond the scope of general practitioners. Existing FFs originate from only a limited number of groups and organizations, and they either suffer from limited numbers of training sets, lower than desired quality because of oversimplified representations, or are costly for the molecular modeling community to access. To address these issues, in this work, we developed an AMBER-consistent small molecule FF with extensive chemical space coverage, and we provide Open Access parameters for the entire modeling community. To validate our FF, we carried out benchmarks of quantum mechanics (QM)/molecular mechanics conformer comparison and free energy perturbation calculations on several benchmark data sets. Our FF achieves a higher level of performance at reproducing QM energies and geometries than two popular open-source FFs, OpenFF2 and GAFF2. In relative binding free energy calculations for 31 protein-ligand data sets, comprising 1079 pairs of ligands, the new FF achieves an overall root-mean-square error of 1.19 kcal/mol for ΔΔ and 0.92 kcal/mol for Δ on a subset of 463 ligands without bespoke fitting to the data sets. The results are on par with those of the leading commercial series of OPLS FFs.
生物分子模拟已成为当代药物发现的重要工具,而分子力学力场 (FF) 则构成了其基石。开发高质量且广泛涵盖的通用 FF 是一项重大任务,需要大量的专业知识和计算资源,这超出了普通从业者的能力范围。现有的 FF 仅源于有限数量的小组和组织,它们要么受到训练集数量有限的限制,要么由于表示过于简化而导致质量不如预期,要么对分子建模社区来说访问成本过高。为了解决这些问题,在这项工作中,我们开发了一种具有广泛化学空间覆盖范围的与 AMBER 一致的小分子 FF,并为整个建模社区提供了开放访问参数。为了验证我们的 FF,我们对几个基准数据集进行了量子力学 (QM)/分子力学构象比较和自由能微扰计算的基准测试。与两个流行的开源 FF(OpenFF2 和 GAFF2)相比,我们的 FF 在再现 QM 能量和几何形状方面表现更为出色。在对包含 1079 对配体的 31 个蛋白-配体数据集进行相对结合自由能计算时,新的 FF 在没有对数据集进行专门拟合的情况下,对于 463 个配体子集,ΔΔ 的总体均方根误差为 1.19 kcal/mol,Δ 为 0.92 kcal/mol。其结果与领先的 OPLS FF 商业系列相当。
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