HLA-B51 ve HLA-B52'nin karşılaştırmalı moleküler dinamik çalışması: HLA-B51'in Behçet Hastalığı'ndaki patojenik rolü üzerine bulgular

Beh çet's Disease (BD) is a chronic inflammatory disorder and its aetiology is unknown. Nearly every genetic study related to BD has confi rmed the association of HLA-B51 with BD since the time the association was first recognized forty years ago. Despite the recurrent affi rmation of HLA-B51 as the strongest genetic risk factor in BD, the exact mechanism of action of HLA-B51 is still unknown. Even though BD is strongly associated with HLA-B51, it is found to be not associated with HLA-B52, which diff ers from HLA-B51 by only two residues found on the peptide-binding region. In order to understand the eff ect of these variations on the dynamics of the bound and unbound forms of the two proteins, we performed comparative molecular dynamics simulations on the two MHC class I proteins in the absence and presence of sixteen diff erent peptides. Distance distribution analysis showed that peptide binding results in a shift to a more coherent conformation in HLA-B52, while there is no signifi cant conformational shift in -B51. Atomic fluctuation analysis additionally showed that peptide binding makes HLA-B52 more stable, which is the expected case, whereas it does not have such an e ffect on -B51. Based on these observations, we speculate that the instability and floppiness of the overall peptide-bound structure of mature HLA-B51 molecules may contribute to its pathogenic role in BD, by causing ER stress induced proinflammatory signaling through unfolded protein response (UPR).