Conformational flexibility of a free and TCR-bound pMHC-I protein investigated by long-term molecular dynamics simulations

Abstract

Background Major histocompatibility complexes (MHCs) play a crucial role in the cell-mediated adaptive immune response as they present antigenic peptides (p) which are recognized by host T cells through a complex formation of the T cell receptor (TCR) with pMHC. In the present study, we report on changes in conformational flexibility within a pMHC molecule upon TCR binding by looking at molecular dynamics (MD) simulations of the free and the TCR-bound pMHC-I protein of the LC13-HLA-B*44:05-pEEYLQAFTY complex. Results We performed long-term MD simulations with a total simulation time of 8 µs, employing 10 independent 400 ns replicas for the free and the TCR-bound pMHC system. Upon TCR ligation, we observed a reduced dynamic flexibility in the central residues of the peptide and the MHC α1-helix, altered occurrences of hydrogen bonds between the peptide and the MHC, a reduced conformational entropy of the peptide-binding groove, as well as a decreased solvent accessible surface area. Conclusions In summary, our results from 8 µs MD simulations indicate a restricted conformational space of the MHC peptide-binding groove upon TCR ligation and suggest a minimum simulation time of approximately 100 ns for biomolecules of comparable complexity to draw meaningful conclusions. Given the relatively long total simulation time, our results contribute to a more detailed view on conformational flexibility properties of the investigated free and TCR-bound pMHC-I system.

Polymorphism in F pocket affects peptide selection and stability of type 1 diabetes‐associated HLA‐B39 allotypes

“…Expanding the peptide selection to encompass a broader range of affinities could provide deeper insights into the dynamics and thermal stability of HLA-B-peptide complexes. It should also be noted that mechanisms other than the peptide-binding affinity and stability of HLA may play important roles in determining the outcome of the adaptive immune response, such as differences in global dynamics and flexibility of pHLA [43][44][45][46][47], mode of peptide presentation [48], and allosteric effects that propagate from the TCR-HLA binding interface to the constant domains of TCR as well as to the alpha-3 domain [49,50]. Such effects were not considered in this work.…”