Understanding the structural dynamics of TCR-pMHC interactions

•TCR–pMHC dynamics are important determinants of T cell recognition and activation.•Molecular dynamic (MD) simulations add a fourth dimension – time – complementing structural studies.•Combining MD and experimental approaches can shed new light into TCR–pMHC interactions.

Dynamics plays an important but underappreciated role in the interaction between the T cell receptor (TCR) and peptide-bound major histocompatibility complex (pMHC). Crystallographic studies have provided key molecular insights into this interaction; however, due to inherent features of the structural approach, the image of TCR–pMHC interactions that has emerged is a static one. In this review, we discuss how molecular dynamics (MD) simulations can complement and extend current experimental methods aimed at examining TCR–pMHC dynamics. We review the insights obtained from studies that leverage MD approaches, and propose that an integrative strategy that harnesses both MD simulations and structural and biophysical methods will provide new inroads into understanding the transitory and dynamic molecular events that dictate TCR signaling and T cell activation.