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

• Published in: BMC immunology Vol. 23; no. Suppl 1; pp. 36 - 13
• Main Authors: Tomasiak, Lisa, Karch, Rudolf, Schreiner, Wolfgang
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 29-07-2022; BioMed Central; BMC
• Subjects: Adaptive immunity; Analysis; Antigen receptors, T cell; Entropy; Flexibility; Histocompatibility antigen HLA; Histocompatibility Antigens; HLA histocompatibility antigens; Hydrogen bonding; Immune response; Immune response (cell-mediated); Lymphocytes T; Major histocompatibility complex; Methods; Molecular dynamics; Molecular Dynamics Simulation; Peptides; Peptides - metabolism; Protein Binding; Protein Conformation; Protein structure; Proteins; Receptors; Receptors, Antigen, T-Cell - metabolism; Simulation; T cell receptor; T cell receptors; T cells; Testing; Austria; Molecular dynamics; Major histocompatibility complex; T cell receptor
• ISSN: 1471-2172; 1471-2172
• DOI: 10.1186/s12865-022-00510-7

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.
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.
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.