化学学报 ›› 2013, Vol. 71 ›› Issue (09): 1313-1320.DOI: 10.6023/A13040393 上一篇    下一篇

研究论文

抗原肽与MHC分子相互作用QM/MM分子动力学模拟研究

冯石磊, 胡墅, 刘兵, 刘伟   

  1. 大连理工大学高科技研究院 大连 116023
  • 投稿日期:2013-04-11 发布日期:2013-06-27
  • 通讯作者: 刘伟,E-mail:jchjys@dlut.edu.cn;Tel.:0411-84707872 E-mail:jchjys@dlut.edu.cn

QM/MM Molecular Dynamics Simulation for the MHC class I Molecule Interacting with Antigen Peptide

Feng Shilei, Hu Shu, Liu Bing, Liu Wei   

  1. College of Advanced Science and Technology, Dalian University of Technology, Dalian 116023
  • Received:2013-04-11 Published:2013-06-27

在MHC I类(major histocompatibility complex class I)分子抗原加工提呈过程中抗原蛋白在抗原提呈细胞(antigen-presenting cells, APC)的胞浆中被蛋白酶体(proteasome)裂解成短肽peptide, 由转运相关蛋白(transporter associated with antigen processing, TAP)将蛋白酶体裂解产生的短肽片段从胞浆转运至内质网腔. 短肽peptide在内质网中与新生成的MHC I类分子结合, 形成peptide-MHC复合体被提呈到APC细胞表面, 与T细胞表面抗原受体(T cell receptor, TCR)特异性识别结合, 使得CTL细胞开始活化、增殖、分化, 进而对肿瘤细胞进行特异性杀伤. 目前对CTL细胞如何识别抗原肽-MHC复合物分子及抗原短肽peptide如何与主要组织相容性复合体MHC分子的相互作用识别结合的机理还不是很清楚. 传统的预测CTL细胞表位的方法没有考虑受体与配体结合过程中电子结构的变化, 电子结构的变化需要用量子力学方法来处理. 本文采用QM/MM多尺度生物大分子的分子动力学模拟方法, 以天然抗原肽TAX (LLFGYPVYVYU)与HLA-A*0201分子结合的晶体结构为模板, 替换抗原肽“锚点”氨基酸, 将口袋氨基酸残基的原子极化电荷在空间形成的静电势用电多极矩分量表示. 用箱线图分析每个口袋氨基酸分子静电势变化和功能, 确定Pocket B的Glu63和Lys66的功能是精细识别氨基酸和一级结合氨基酸, Pocket F的Asp77, Tyr84的功能是精细识别氨基酸, 而Asp77, Lys146是一级结合氨基酸, 表明QM/MM方法在提取抗原肽与MHC I类分子识别结合特异性信息是可行的, 这对了解免疫识别机理和指导肿瘤疫苗的开发都具有指导意义.

关键词: QM/MM分子动力学模拟, 电多极矩, T细胞表位, 外源性抗原, MHC I类分子

In the process of antigen presenting of major histocompatibility complex (MHC) class I molecule, antigen protein, which is in the cytoplasm of antigen-presenting cells (APC), is cleaved into short peptide fragments by proteasome, and the short peptide fragments will be transferred from the cytoplasm to the endoplasmic reticulum lumen by transporter associated with antigen processing (TAP). The peptide will combine with the MHC class I molecule, and the forming pMHC complex will be presented to the surface of APC cells, and it will be recognized by T cell receptor (TCR). And then, the CTL cells will be activated, and it will begin to proliferate and differentiate, and it will kill the tumor cells. The mechanisms how does the CTL cell recognize the peptide-MHC complex and how does the MHC molecule interact with the peptide are not clear. In traditional method, electronic structure changes is not considered during the peptide binding to the MHC molecules. The electronic structure changes need to use the method of Quantum Mechanics to deal with. In this paper, we use QM/MM multi-scale molecular dynamics simulation of biological macromolecules, and take the crystal structure of TAX-HLA- A*0201 molecules complex as template. We would replace the anchor amino acid of the peptide, and use the electric multipole moment component to present the electrostatic potential formed by the atomic polarization charge of pocket amino acid residues. We analyze the electrostatic potential changes and the functions of each pocket amino acid by box plots, we would consider that Glu63 and Lys66 of Pocket B are primary anchoring amino acids and fine recognition amino acid, Asp77 and Tyr84 of Pocket F are the fine recognition amino acid, Asp77 and Lys146 are the primary anchoring amino acids. It shows that QM/MM method is very effective in extracting the specific information of antigen peptide binding to MHC class I molecules. And it possesses some guiding significance to understand the mechanism of immune recognition and the development of tumor vaccine.

Key words: QM/MM molecular dynamic simulation, electric multipole moment, T cell epitope, exogenous antigen, MHC class I molecules