发表机构
Indian Institute of Technology Madras（印度马德拉斯理工大学）
机构由 AI 辅助整理，请以论文原文为准。AI 中文总结
本研究结合生物信息学、分子动力学模拟与机器学习，开发DynamiT模型，明确影响T细胞活化的关键因素，可用于筛选病毒表位以助力疫苗开发。
AI 中文摘要
T细胞免疫是脊椎动物抵御和控制病毒感染的主要防御系统。病毒入侵期间，先天免疫细胞会降解病毒蛋白（抗原），并通过主要组织相容性（MHC）蛋白将这些抗原呈递至细胞表面；T细胞受体（TCR）识别由MHC呈递的这些抗原/肽（即pMHC），进而启动T细胞介导的免疫应答。尽管该过程至关重要，但pMHC-TCR结合触发T细胞活化的机制仍不明确。本研究采用整合计算方法，结合生物信息学、分子动力学（MD）模拟和机器学习（ML）技术，以识别可作为潜在疫苗候选物的病毒表位。研究人员对嵌入树突状细胞和T细胞中的MHC-肽-TCR复合物开展大规模全原子与粗粒度MD模拟，这些复合物具备可用的实验免疫原性数据；共对150个此类系统各进行1微秒（1 μs）的模拟，以捕捉构成T细胞活化基础的构象与动力学变化。研究人员基于从2500个时间点提取的模拟衍生结构与动力学特征训练ML模型（DynamiT），该模型揭示了负责T细胞活化的关键决定因素，准确率达73.3%。值得注意的是，研究人员确定了TCR跨膜区的弯曲、TCRα恒定区的主要动态运动以及pMHC与TCR界面的埋藏表面积是影响免疫应答启动的关键因素。本研究方法阐明了T细胞介导免疫应答的机制，并助力ML引导的病毒表位筛选以用于疫苗开发。
英文摘要
T-cell immunity acts as a major defense system against controlling viral infections in vertebrates. During viral entry, innate immune cells degrade the viral proteins (antigens) and present them on their surface via Major Histocompatibility (MHC) proteins. T-cell receptors (TCRs) recognize these antigens/peptides presented by MHC (pMHC), initiating a T-cell mediated immune response. Despite its significance, the mechanism by which pMHC-TCR binding triggers T-cell activation remains unclear. In this study, we employed an integrative computational approach combining Bioinformatics, Molecular Dynamics (MD) simulations, and Machine Learning (ML) to identify viral epitopes as potential vaccine candidates. We performed large-scale all-atom and coarse-grained MD simulations on MHC-peptide-TCR complexes embedded into dendritic and T-cells, for which experimental immunogenicity data is available. One hundred fifty such systems are simulated for 1 μs each to capture the conformational and dynamical changes that underlie T-cell activation. Our ML model (DynamiT), trained on simulation-derived structural and dynamical features extracted from 2500 time points, revealed key determinants responsible for T-cell activation with an accuracy of 73.3%. Notably, we have identified the bending of the TCR transmembrane region, major dynamic motions of the TCRα constant region and the buried surface area at the pMHC and TCR interface as critical factors influencing immune response initiation. Our approach unravels the mechanism of T-cell mediated immune response and helps ML-guided screening of viral epitopes for vaccine development.
