N-Terminal-Driven Binding Mechanism of an Antigen Peptide to Human Leukocyte Antigen-A*2402 Elucidated by Multicanonical Molecular Dynamic-Based Dynamic Docking and Path Sampling Simulations
N-Terminal-Driven Binding Mechanism of an Antigen Peptide to Human Leukocyte Antigen-A*2402 Elucidated by Multicanonical Molecular Dynamic-Based Dynamic Docking and Path Sampling Simulations
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DOI：
10.1021/acs.jpcb.1c07230
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发表时间：
2021-12-16
影响因子：
3.3
通讯作者：
Kamiya, Narutoshi
中科院分区：
文献类型：
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作者：
Bekker, Gert-Jan;Kamiya, Narutoshi
我们应用我们先进的基于多克隆分子动力学(MCMD)的动态对接方法来研究HIV-1Nef蛋白表位与亚洲占优势的等位基因人类白细胞抗原(HLA)-A*2402的结合机制。尽管pMHC复合体的形成是人类获得性免疫反应的基本过程之一，但其结合机制尚未得到很好的研究，部分原因是由于HLAs在人群中的高度等位基因变异。我们使用了我们开发的基于MCMD的动态对接方法，并成功地再现了位于自由能全局极小值附近的天然复杂结构。随后的路径采样MD模拟阐明了结合过程的原子细节，并表明多肽结合最初是由多肽的高正电荷N末端驱动的，该末端被MHC分子表面的各种负电荷残基吸引。当接近口袋时，肽的第二个酪氨酸残基通过疏水驱动的相互作用与MHC分子的B位强烈结合，从而形成非常强的结合复杂结构。我们的方法可以有效地预测MHC分子与其抗原之间的结合复杂结构，以详细研究其结合机制，这将有助于开发针对癌症以及艾滋病毒和新冠肺炎等病毒感染的新疫苗。
We have applied our advanced multicanonical molecular dynamics (McMD)-based dynamic docking methodology to investigate the binding mechanism of an HIV-1 Nef protein epitope to the Asian-dominant allele human leukocyte antigen (HLA)-A*2402. Even though pMHC complex formation [between a Major histocompatibility complex (MHC) class I molecule, which is encoded by an HLA allele, and an antigen peptide] is one of the fundamental processes of the adaptive human immune response, its binding mechanism has not yet been well studied, partially due to the high allelic variation of HLAs in the population. We have used our developed McMD-based dynamic docking method and have successfully reproduced the native complex structure, which is located near the free energy global minimum. Subsequent path sampling MD simulations elucidated the atomic details of the binding process and indicated that the peptide binding is initially driven by the highly positively charged N-terminus of the peptide that is attracted to the various negatively charged residues on the MHC molecule's surface. Upon nearing the pocket, the second tyrosine residue of the peptide anchors the peptide by strongly binding to the B-site of the MHC molecule via hydrophobic driven interactions, resulting in a very strong bound complex structure. Our methodology can be effectively used to predict the bound complex structures between MHC molecules and their antigens to study their binding mechanism in close detail, which would help with the development of new vaccines against cancers, as well as viral infections such as HIV and COVID-19.