The Role of Vimentin Peptide Citrullination in the Structure and Dynamics of HLA-DRB1 Rheumatoid Arthritis Risk-Associated Alleles

Citrullination, a post-translational modification (PTM), plays a critical role in rheumatoid arthritis (RA) by triggering immune responses to citrullinated self-antigens. Some HLA-DRB1 genes encode molecules with the shared epitope (QKRAA/QRRAA) sequence in the peptide-binding groove which preferentially presents citrulline-modified peptides, like vimentin, that intensifies the immune response in RA. In this study, we used computational approaches to evaluate intermolecular interactions between vimentin peptide-ligands (with/without PTM) and HLA-DRB1 alleles associated with a significantly increased risk for RA development. Crystal structures for HLA-DRB1*04:01, *04:04, and *04:05 bound to citrullinated peptides (PDB ID: 4MCY, 4MD5, 6BIR) were retrieved from the Protein Data Bank and non-citrullinated 3D structures were generated by mutating citrulline to arginine. The pHLA complexes were submitted to four rounds (50 ns each) of molecular dynamic simulations (MD) with Gromacs v.2022. Our results show that citrulline strengthens the interaction between vimentin and the HLA-DRB1 molecules, therefore impacting both the peptide affinity to the HLAs and pHLA stability; it also induces more intermolecular hydrogen bond formation during MD in the pHLA. Citrulline prevents repulsion between amino acid 71β and the P4-residue of native vimentin. Thus, vimentin citrullination seems to affect pHLA binding and dynamics, which may influence RA-related immune responses.