高等学校化学学报2017，Vol.38Issue(11)：2070-2076,7.DOI:10.7503/cjcu20170212
力场/溶剂水模型对EGFRvⅢ抗原-MR1(scFv)抗体复合物的MM-PBSA计算精度的影响与实验验证
Effect of Force Fields and Water Models on EGFRvⅢ-MR1( scFv) Complex by Molecular Dynamics Simulation, MM-PBSA Calculation, and ITC Experiment
摘要
Abstract
Six commonly used force fields and three commonly used solvent water models were employed, respectively, for EGFRvⅢand its corresponding scFv antibody( MR1) complex, and total 16 antigen-antibody complex moleaular( MD) simulations were carried out. The molecular mechanics/Poisson-Boltzmann surface area ( MM-PBSA ) calculations were performed and the thermodynamic parameters of antigen-antibody interaction were measured by isothermal titration calorimetry( ITC) experiment. The RMSD analysis show that all the MD simulations were stable, but the binding free energy values from MM-PBSA are different under 6 force fields and 3 water models. The recommended calculation models are given by comprehensive analysis of structural changes, energy changes, consistency of experiment and combining calculation and experimental verification with two antibody humanization mutants ( huMR1-2 and huMR1-G ) . At the same time, the calculation accuracy of different force fields and solvent water models were discussed. The conclusions of this study can be used in the subsequent antibody humanization, antibody affinity maturation, and other related computer-aided antibody drug design.关键词
单链抗体/分子动力学模拟/分子力学和连续介质模型的自由能计算/等温滴定量热/均方根偏差Key words
Single-chain variable fragment ( scFv )/Molecular dynamics ( MD ) simulation/Molecular mechanics/Poisson-Boltzmann surface area(MM-PBSA)/Isothermal titration calorimetry(ITC)/Root mean square deviation( RMSD)分类
化学化工引用本文复制引用
任家毅,袁晓辉,欧仕益,杨志伟,郑念珏,李军旗,杨春龙,林淑健,杨冰,黄俊卿,廖化新..力场/溶剂水模型对EGFRvⅢ抗原-MR1(scFv)抗体复合物的MM-PBSA计算精度的影响与实验验证[J].高等学校化学学报,2017,38(11):2070-2076,7.基金项目
国家自然科学基金(批准号:31400795)、 广东省引进创新创业团队专项(批准号:2013Y113)、 广州市珠江科技新星专项(批准号:201506010097)、 广东省计算科学重点实验室开放基金(批准号:2016004)和广东省生物工程药物重点实验室运行经费(批准号:2014B030301050)资助.Supported by the National Natural Science Foundation of China(No.31400795), the Guangdong Innovative and Entrepreneurial Research Team Program, China(No.2013Y113), the Pearl River S&T Nova Program of Guangzhou, China(No.201506010097), the Opening Project of Guangdong Province Key Laboratory of Computational Science at the Sun Yat-sen University, China( No. 2016004) and the Operating Fund of Guangdong Provincial Key Laboratory of Bioengineering Medicine, China( No.2014B03, 0301050) . （批准号:31400795）
