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This study employs an integrative computational approach that combines bioinformatics, molecular dynamics simulations, and machine learning to elucidate the mechanisms of T-cell activation via pMHC-TCR binding. By simulating 150 MHC-peptide-TCR complexes and analyzing their structural dynamics, the researchers identified critical determinants of T-cell activation, achieving a predictive accuracy of 73.3% with their ML model, DynamiT. The findings highlight the importance of specific conformational changes in the TCR and its interactions with pMHC, which could guide the identification of viral epitopes for vaccine development.
The bending of the TCR transmembrane region is a key factor that could revolutionize our understanding of T-cell activation and vaccine design.
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 {\mu}s 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 TCR{\alpha} 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.