Chang-Gonzalez Ana C, Mallis Robert J, Lang Matthew J, Reinherz Ellis L, Hwang Wonmuk
Department of Biomedical Engineering, Texas A&M University, College Station, TX, USA.
Dept. Dermatology, Harvard Medical School, Boston, MA, USA.
bioRxiv. 2023 Sep 13:2023.09.10.557064. doi: 10.1101/2023.09.10.557064.
Mechanical force is critical for the interaction between an T cell receptor (TCR) and a peptide-bound major histocompatibility complex (pMHC) molecule to initiate productive T-cell activation. However, the underlying mechanism remains unclear. We use all-atom molecular dynamics simulations to examine the A6 TCR bound to HLA-A*02:01 presenting agonist or antagonist peptides under different extensions to simulate the effects of applied load on the complex, elucidating their divergent biological responses. We found that TCR and chains move asymmetrically, which impacts the interface with pMHC, in particular the peptide-sensing CDR3 loops. For the wild-type agonist, the complex stabilizes in a load-dependent manner while antagonists destabilize it. Simulations of the C FG-loop deletion, which reduces the catch bond response, and simulations with mutant peptides further support the observed behaviors. The present results highlight the combined role of interdomain motion, fluctuating forces, and interfacial contacts in determining the mechanical response and fine peptide discrimination by a TCR, thereby resolving the conundrum of nearly identical crystal structures of TCR-pMHC agonist and antagonist complexes.
机械力对于T细胞受体（TCR）与肽结合的主要组织相容性复合体（pMHC）分子之间的相互作用至关重要，可启动有效的T细胞活化。然而，其潜在机制仍不清楚。我们使用全原子分子动力学模拟来研究与HLA-A*02:01结合的A6 TCR，该复合体呈现激动剂或拮抗剂肽，处于不同的伸展状态，以模拟施加的负荷对复合体的影响，阐明它们不同的生物学反应。我们发现TCR的α和β链不对称移动，这会影响与pMHC的界面，特别是肽感知CDR3环。对于野生型激动剂，复合体以负荷依赖的方式稳定，而拮抗剂则使其不稳定。对减少捕获键反应的C FG环缺失的模拟，以及对突变肽的模拟，进一步支持了观察到的行为。目前的结果突出了结构域间运动、波动的力和界面接触在决定TCR的机械反应和精细肽识别中的联合作用，从而解决了TCR-pMHC激动剂和拮抗剂复合体几乎相同的晶体结构这一难题。
