The mechanical response of the interaction between the T cell receptor (TCR) and the peptide major histocompatibility complex (pMHC) is fundamental to antigen recognition, but the atomic-scale mechanisms by which the CD8 coreceptor modulates the complex's conformational states and force-bearing behavior remain poorly understood. We employed all-atom molecular dynamics and steered molecular dynamics simulations of membrane-embedded TCR-pMHC and TCR-pMHC-CD8 complexes to characterize their dynamics and force-induced dissociation. Microsecond-long molecular dynamics (MD) simulations show that binding of CD8 to the MHC alpha3 domain applies restraints to the latter one, which leads the MHC alpha1 helix to stably bind against the TCR complementarity-determining regions (CDRs) and suppressing the fluctuations of the antigenic peptide. Furthermore, under mechanical loading, the TCR-pMHC-CD8 system exhibits a distinct dissociation pathway compared to that of the TCR-pMHC complex, which may strengthen the mechanical stability of the binding of TCR-pMHC. Collectively, these findings unravel the molecular mechanisms of CD8-mediated synergistic stabilization and mechanical regulation of TCR-pMHC, providing new mechanistic insights into coreceptor-dependent T cell antigen recognition.
Li, J., Li, Z.
Advertisement
Stats
- Recommendations n/a n/a positive of 0 vote(s)
- Views 2
- Comments 0