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

doi:10.7503/cjcu20170212

高等学校化学学报 ›› 2017, Vol. 38 ›› Issue (11): 2070.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

任家毅¹, 杨志伟², 郑念珏^3,⁴, 李军旗³, 杨春龙⁴, 林淑健³, 杨冰³, 黄俊卿¹, 廖化新^3,⁶, 袁晓辉^3,^6,⁷(), 欧仕益⁵()

1. 暨南大学中医学院, 广州 510632
2. 西安交通大学理学院, 西安 710049
3. 暨南大学生物医药研究院, 广州 510632
4. 广州中医药大学顺德医院, 顺德 528300
5. 暨南大学食品科学与工程系, 广州 510632
6. 广东省生物工程药物重点实验室, 广州 510632
7. 基因工程药物国家工程研究中心, 广州 510632

收稿日期:2017-04-11 出版日期:2017-11-10 发布日期:2017-10-30
作者简介:联系人简介: 袁晓辉, 男, 博士, 副研究员, 主要从事生物大分子模拟研究. E-mail: yuanhui1024@gmail.com。欧仕益, 男, 博士, 教授, 主要从事食品化学研究. E-mail: tosy@jnu.edu.cn
基金资助:
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

Effect of Force Fields and Water Models on EGFRvⅢ-MR1(scFv)Complex by Molecular Dynamics Simulation, MM-PBSA Calculation, and ITC Experiment^†

REN Jiayi¹, YANG Zhiwei², ZHENG Nianjue^3,⁴, LI Junqi³, YANG Chunlong⁴, LIN Shujian³, YANG Bing³, HUANG Junqing¹, LIAO Huaxin^3,⁶, YUAN Xiaohui^3,^6,^7,^*(), OU Shiyi^5,^*()

1. Chinese Medicine College, Jinan University, Guangzhou 510632, China
2. School of Science, Xian Jiaotong University, Xi'an 710049, China
3. Institute of Biomedicine, Jinan University, Guangzhou 510632, China
4. Shunde Hospital of Guangzhou University of Chinese Medicine, Shunde 528300, China
5. Department of Food Science and Engineering, Jinan University, Guangzhou 510632, China
6. Guangdong Provincial Key Laboratory of Bioengineering Medicine, Guangzhou 510632, China
7. National Engineering Research Center of Genetic Medicine, Guangzhou 510632, China

Received:2017-04-11 Online:2017-11-10 Published:2017-10-30
Contact: YUAN Xiaohui,OU Shiyi E-mail:yuanhui1024@gmail.com;tosy@jnu.edu.cn
Supported by:
† 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)

摘要/Abstract

摘要：

以表皮生长因子Ⅲ型突变体(EGFRvⅢ)抗原多肽与其抗体(MR1)及其人源化突变体的复合物结构为出发点, 采用分子动力学中的6种常用力场及3种常用溶剂水模型, 分别对上述抗原-抗体复合物进行100 ns的分子动力学模拟与分子力学和连续介质模型计算自由能(MM-PBSA), 并在实验上利用等温滴定量热(ITC)仪测定了抗原和抗体相互作用的热力学参数. 通过在结构变化、能量变化及野生型与突变体比较等几个方面进行综合分析, 给出了最佳的计算模型. 对不同力场及水模型计算精度等相关问题进行了探讨.

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

Abstract:

Six commonly used force fields and three commonly used solvent water models were employed, respectively, for EGFRvⅢ and 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.

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)

中图分类号:

O641

TrendMD:

任家毅, 杨志伟, 郑念珏, 李军旗, 杨春龙, 林淑健, 杨冰, 黄俊卿, 廖化新, 袁晓辉, 欧仕益. 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. 高等学校化学学报, 2017, 38(11): 2070.

REN Jiayi, YANG Zhiwei, ZHENG Nianjue, LI Junqi, YANG Chunlong, LIN Shujian, YANG Bing, HUANG Junqing, LIAO Huaxin, YUAN Xiaohui, OU Shiyi. Effect of Force Fields and Water Models on EGFRvⅢ-MR1(scFv)Complex by Molecular Dynamics Simulation, MM-PBSA Calculation, and ITC Experiment^†. Chem. J. Chinese Universities, 2017, 38(11): 2070.

图/表 7

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Model	ΔE_elec/(kJ·mol^-1)	ΔE_vdw/(kJ·mol^-1)	ΔG_PB/(kJ·mol^-1)	ΔG_SA/(kJ·mol^-1)	ΔG_binding/(kJ·mol^-1)
amber03_spce	-2518.735	-295.524	2767.561	-28.855	-75.553±3.758
amber03_tip3p	-2874.299	-304.486	3173.377	-29.418	-34.826±3.443
amber03_tip4p	-2702.526	-290.906	3030.706	-28.663	8.610±5.950
charmm27_spce	-2492.866	-238.037	2713.931	-27.975	-44.947±6.075
charmm27_tip3p	-2303.727	-233.229	2468.832	-26.908	-95.031±4.623
charmm27_tip4p	-2800.433	-242.833	3043.32	-27.453	-27.399±7.106
gromos96-54a7	-2446.944	-252.682	2709.011	-27.904	-18.520±5.093
amber99sb_spce	-2528.417	-278.065	2789.872	-26.607	-43.218±3.088
amber99sb_tip3p	-2971.318	-295.934	3207.616	-29.787	-89.423±3.881
amber99sb_tip4p	-2407.973	-266.857	2619.559	-26.812	-82.084±4.657
amber99sb-ildn_spce	-2891.773	-273.324	3097.473	-29.150	-96.773±4.434
amber 99sb-ildn_tip3p	-2892.162	-273.536	3097.309	-29.157	-97.546±4.335
amber 99sb-ildn_tip4p	-2867.603	-275.969	3141.154	-28.163	-30.582±4.665
opls-aa/L_spce	-2623.759	-203.696	2856.112	-27.613	1.044±3.825
opls-aa/L_tip3p	-2863.741	-211.183	3126.996	-28.695	23.377±5.704
opls-aa/L_tip4p	-2751.395	-204.802	3036.047	-27.298	52.552±5.585

Model	ΔE_elec/(kJ·mol^-1)	ΔE_vdw/(kJ·mol^-1)	ΔG_PB/(kJ·mol^-1)	ΔG_SA/(kJ·mol^-1)	ΔG_binding/(kJ·mol^-1)
amber03_spce	-2518.735	-295.524	2767.561	-28.855	-75.553±3.758
amber03_tip3p	-2874.299	-304.486	3173.377	-29.418	-34.826±3.443
amber03_tip4p	-2702.526	-290.906	3030.706	-28.663	8.610±5.950
charmm27_spce	-2492.866	-238.037	2713.931	-27.975	-44.947±6.075
charmm27_tip3p	-2303.727	-233.229	2468.832	-26.908	-95.031±4.623
charmm27_tip4p	-2800.433	-242.833	3043.32	-27.453	-27.399±7.106
gromos96-54a7	-2446.944	-252.682	2709.011	-27.904	-18.520±5.093
amber99sb_spce	-2528.417	-278.065	2789.872	-26.607	-43.218±3.088
amber99sb_tip3p	-2971.318	-295.934	3207.616	-29.787	-89.423±3.881
amber99sb_tip4p	-2407.973	-266.857	2619.559	-26.812	-82.084±4.657
amber99sb-ildn_spce	-2891.773	-273.324	3097.473	-29.150	-96.773±4.434
amber 99sb-ildn_tip3p	-2892.162	-273.536	3097.309	-29.157	-97.546±4.335
amber 99sb-ildn_tip4p	-2867.603	-275.969	3141.154	-28.163	-30.582±4.665
opls-aa/L_spce	-2623.759	-203.696	2856.112	-27.613	1.044±3.825
opls-aa/L_tip3p	-2863.741	-211.183	3126.996	-28.695	23.377±5.704
opls-aa/L_tip4p	-2751.395	-204.802	3036.047	-27.298	52.552±5.585

Model	Complex	ΔE_elec/(kJ·mol^-1)	ΔE_vdw/(kJ·mol^-1)	ΔG_PB/(kJ·mol^-1)	ΔG_SA/(kJ·mol^-1)
amber99sb_spce	EGFRvⅢ-MR1	-2528.417	-278.065	2789.872	-26.607
	EGFRvⅢ-huMR1-2	-2162.511	-246.557	2441.200	-28.582
	EGFRvⅢ-huMR1-G	-2609.293	-265.212	2859.976	-26.456
amber03_tip3p	EGFRvⅢ-MR1	-2874.299	-304.486	3173.377	-29.418
	EGFRvⅢ-huMR1-2	-2407.570	-232.322	2692.079	-29.635
	EGFRvⅢ-huMR1-G	-2700.723	-294.043	2987.091	-28.713

Model	Complex	ΔE_elec/(kJ·mol^-1)	ΔE_vdw/(kJ·mol^-1)	ΔG_PB/(kJ·mol^-1)	ΔG_SA/(kJ·mol^-1)
amber99sb_spce	EGFRvⅢ-MR1	-2528.417	-278.065	2789.872	-26.607
	EGFRvⅢ-huMR1-2	-2162.511	-246.557	2441.200	-28.582
	EGFRvⅢ-huMR1-G	-2609.293	-265.212	2859.976	-26.456
amber03_tip3p	EGFRvⅢ-MR1	-2874.299	-304.486	3173.377	-29.418
	EGFRvⅢ-huMR1-2	-2407.570	-232.322	2692.079	-29.635
	EGFRvⅢ-huMR1-G	-2700.723	-294.043	2987.091	-28.713

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^†

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