Factors That Affect the Computational Prediction of Hot Spots in Protein-Protein Complexes

作     者：Jianping Lin Pi Liu Hua-Zheng Yang Nagarajan Vaidehi 

作者机构：College of Pharmacy Nankai University Tianjin China Department of Immunology Beckman Research Institute of the City of Hope Duarte USA State Key Laboratory of Elemento-Organic Chemistry Elemento-Organic Chemistry Institute Nankai University Tianjin China 

出 版 物：《Computational Molecular Bioscience》 (计算分子生物学（英文）)

年 卷 期：2012年第2卷第1期

页      面：23-34页

学科分类：1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学] 

主　　题：Hotspot Prediction Computational Mutagenesis Concoord Ensemble Protein-Protein Complexes 

摘      要：Protein-protein complexes play an important role in the physiology and the pathology of cellular functions, and therefore are attractive therapeutic targets. A small subset of residues known as “hot spots, accounts for most of the protein-protein binding free energy. Computational methods play a critical role in identifying the hotspots on the proteinprotein interface. In this paper, we use a computational alanine scanning method with all-atom force fields for predicting hotspots for 313 mutations in 16 protein complexes of known structures. We studied the effect of force fields, solvation models, and conformational sampling on the hotspot predictions. We compared the calculated change in the protein-protein interaction energies upon mutation of the residues in and near the protein-protein interface, to the experimental change in free energies. The AMBER force field (FF) predicted 86% of the hotspots among the three commonly used FF for proteins, namely, AMBER FF, Charmm27 FF, and OPLS-2005 FF. However, AMBER FF also showed a high rate of false positives, while the Charmm27 FF yielded 74% correct predictions of the hotspot residues with low false positives. Van der Waals and hydrogen bonding energy show the largest energy contribution with a high rate of prediction accuracy, while the desolvation energy was found to contribute little to improve the hot spot prediction. Using a conformational ensemble including limited backbone movement instead of one static structure leads to better predicttion of hotpsots.