Large-Scale Analysis of Bioactive Ligand Conformational Strain Energy by Ab Initio Calculation

蛋白质数据库 分子内力 化学 从头算 分子力学 晶格能 能量最小化 分子动力学 结晶学 配体(生物化学) 计算化学 晶体结构 立体化学 有机化学 受体 生物化学
作者
Jiahui Tong,Suwen Zhao
出处
期刊:Journal of Chemical Information and Modeling [American Chemical Society]
卷期号:61 (3): 1180-1192 被引量:23
标识
DOI:10.1021/acs.jcim.0c01197
摘要

Ligand conformational strain energy (LCSE) plays an important role in virtual screening and lead optimization. While various studies have provided insights into LCSE for small-molecule ligands in the Protein Data Bank (PDB), conclusions are inconsistent mainly due to small datasets, poor quality control of crystal structures, and molecular mechanics (MM) or low-level quantum mechanics (QM) calculations. Here, we built a high-quality dataset (LigBoundConf) of 8145 ligand-bound conformations from PDB crystal structures and calculated LCSE at the M062X-D3/ma-TZVPP (SMD)//M062X-D3/def2-SVP(SMD) level for each case in the dataset. The mean/median LCSE is 4.6/3.7 kcal/mol for 6672 successfully calculated cases, which is significantly lower than the estimates based on molecular mechanics in many previous analyses. Especially, when removing ligands with nonaromatic ring(s) that are prone to have large LCSEs due to electron density overfitting, the mean/median LCSE was reduced to 3.3/2.5 kcal/mol. We further reveal that LCSE is correlated with several ligand properties, including formal atomic charge, molecular weight, number of rotatable bonds, and number of hydrogen-bond donors and acceptors. In addition, our results show that although summation of torsion strains is a good approximation of LCSE for most cases, for a small fraction (about 6%) of our dataset, it underestimates LCSEs if ligands could form nonlocal intramolecular interactions in the unbound state. Taken together, our work provides a comprehensive profile of LCSE for ligands in PDB, which could help ligand conformation generation, ligand docking pose evaluation, and lead optimization.
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