Dynamically Driven Allostery in MHC Proteins: Peptide-Dependent Tuning of Class I MHC Global Flexibility

In conclusion, our results provide new insights into the molecular principles governing peptide-dependent effects on MHC proteins. The data indicates that peptide-dependent impacts not only include but extend well-beyond static changes at the peptide-binding groove surface and suggest that MHC proteins in general are highly tunable sensor proteins primed to modulate immunobiology in sophisticated, dynamic fashions. Materials and Methods Molecular Dynamics Simulations and Analysis The majority of the molecular dynamics data analyzed here were described previous previously (34). Additional simulations unique to this report were performed identically. Briefly, all simulations were generated with the GPU-accelerated version of the AMBER 14 molecular dynamics suite utilizing the ff14SB force field (73–75). Starting coordinates for each simulation were obtained from the Protein Data Bank; when multiple molecules were present in the asymmetric unit, coordinates from the first were used. Terminal residues of the peptide were modeled in their charged state. Missing side chains and residues, usually localized to the α3 domain of the heavy chain, were modeled in using the crystal structure of HLA-A*0201 presenting the Tax peptide (PDB accession code 1DUZ) (39) via Chimera (76). All systems were charge neutralized with sodium counter ions and explicitly solvated with an isometric box of SPC/E water (77) to a minimum of 10 Å from peptide/MHC atoms. Following thi...
Source: Frontiers in Immunology - Category: Allergy & Immunology Source Type: research