Development and Comprehensive Benchmark of a High-Quality AMBER-Consistent Small Molecule Force Field with Broad Chemical Space Coverage for Molecular Modeling and Free Energy Calculation

被引：7

作者：

Xue, Bai ^{[2
]}

Yang, Qingyi ^{[1
]}

Zhang, Qiaochu ^{[2
]}

Wan, Xiao ^{[2
]}

Fang, Dong ^{[2
]}

Lin, Xiaolu ^{[2
]}

Sun, Guangxu ^{[2
]}

Gobbo, Gianpaolo ^{[3
]}

Cao, Fenglei ^{[2
]}

Mathiowetz, Alan M. ^{[1
]}

Burke, Benjamin J. ^{[4
]}

Kumpf, Robert A. ^{[4
]}

Rai, Brajesh K. ^{[5
]}

Wood, Geoffrey P. F. ^{[6
]}

Pickard, Frank C. ^{[6
]}

Wang, Junmei ^{[7
,8
]}

Zhang, Peiyu ^{[2
]}

Ma, Jian ^{[2
]}

Jiang, Yide Alan ^{[3
]}

Wen, Shuhao ^{[2
]}

Hou, Xinjun ^{[1
]}

Zou, Junjie ^{[2
]}

Yang, Mingjun ^{[2
]}

机构：

[1] Pfizer Inc, Med Design, Cambridge, MA 02139 USA

[2] Shenzhen Jingtai Technol Co Ltd XtalPi, Shenzhen 518045, Peoples R China

[3] XtalPi Inc, Cambridge, MA 02142 USA

[4] Pfizer Inc, Med Design, San Diego, CA 92121 USA

[5] Pfizer Inc, Machine Learning & Computat Sci, Cambridge, MA 02139 USA

[6] Pfizer Inc, Pharmaceut Sci Small Mol, Groton, CT 06340 USA

[7] Univ Pittsburgh, Dept Pharmaceut Sci, Pittsburgh, PA 15261 USA

[8] Univ Pittsburgh, Computat Chem Genom Screening Ctr, Pittsburgh, PA 15261 USA

来源：

JOURNAL OF CHEMICAL THEORY AND COMPUTATION | 2023年 / 20卷 / 02期

关键词：

POTENTIAL FUNCTIONS; REPLICA-EXCHANGE; EFFICIENT; DYNAMICS; CHARMM; PREDICTION; ACCURACY; PARAMETERIZATION; INTEGRATION; GENERATION;

D O I：

10.1021/acs.jctc.3c00920

中图分类号：

O64 [物理化学（理论化学）、化学物理学];

学科分类号：

070304 ; 081704 ;

摘要：

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 Delta Delta G and 0.92 kcal/mol for Delta G 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.

引用

页码：799 / 818

页数：20