Assessing the performance of the MM/PBSA and MM/GBSA methods. 6. Capability to predict protein-protein binding free energies and re-rank binding poses generated by protein-protein docking

被引:371
作者
Chen, Fu [1 ]
Liu, Hui [1 ]
Sun, Huiyong [1 ]
Pan, Peichen [1 ]
Li, Youyong [3 ]
Li, Dan [1 ]
Hou, Tingjun [1 ,2 ]
机构
[1] Zhejiang Univ, Coll Pharmaceut Sci, Hangzhou 310058, Zhejiang, Peoples R China
[2] Zhejiang Univ, State Key Lab CAD&CG, Hangzhou 310058, Zhejiang, Peoples R China
[3] Soochow Univ, Inst Funct Nano Soft Mat FUNSOM, Suzhou 215123, Jiangsu, Peoples R China
基金
美国国家科学基金会;
关键词
REFINED CRYSTAL-STRUCTURE; PANCREATIC ALPHA-AMYLASE; 2.5 ANGSTROM RESOLUTION; BOLTZMANN SURFACE-AREA; STRUCTURAL BASIS; FAB FRAGMENT; COMPLEX-FORMATION; DRUGGABILITY PREDICTION; CONFORMATIONAL-CHANGES; COMPUTATIONAL ANALYSIS;
D O I
10.1039/c6cp03670h
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
Understanding protein-protein interactions (PPIs) is quite important to elucidate crucial biological processes and even design compounds that interfere with PPIs with pharmaceutical significance. Protein-protein docking can afford the atomic structural details of protein-protein complexes, but the accurate prediction of the three-dimensional structures for protein-protein systems is still notoriously difficult due in part to the lack of an ideal scoring function for protein-protein docking. Compared with most scoring functions used in protein-protein docking, the Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) and Molecular Mechanics/Poisson Boltzmann Surface Area (MM/PBSA) methodologies are more theoretically rigorous, but their overall performance for the predictions of binding affinities and binding poses for protein-protein systems has not been systematically evaluated. In this study, we first evaluated the performance of MM/PBSA and MM/GBSA to predict the binding affinities for 46 protein-protein complexes. On the whole, different force fields, solvation models, and interior dielectric constants have obvious impacts on the prediction accuracy of MM/GBSA and MM/PBSA. The MM/GBSA calculations based on the ff02 force field, the GB model developed by Onufriev et al. and a low interior dielectric constant (epsilon(in) = 1) yield the best correlation between the predicted binding affinities and the experimental data (r(p) = -0.647), which is better than MM/PBSA (r(p) = -0.523) and a number of empirical scoring functions used in protein-protein docking (r(p) = -0.141 to -0.529). Then, we examined the capability of MM/GBSA to identify the possible near-native binding structures from the decoys generated by ZDOCK for 43 protein-protein systems. The results illustrate that the MM/GBSA rescoring has better capability to distinguish the correct binding structures from the decoys than the ZDOCK scoring. Besides, the optimal interior dielectric constant of MM/GBSA for re-ranking docking poses may be determined by analyzing the characteristics of protein-protein binding interfaces. Considering the relatively high prediction accuracy and low computational cost, MM/GBSA may be a good choice for predicting the binding affinities and identifying correct binding structures for protein-protein systems.
引用
收藏
页码:22129 / 22139
页数:11
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