Molecular dynamics simulations provide molecular insights into the role of HLA-B51 in Behçet's disease pathogenesis

Mert Gur*, Mert Golcuk, Ahmet Gul, Burak Erman

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)

Abstract

Behçet's disease is an inflammatory disorder of unknown etiology. Genetic tendency has an important role in its pathogenesis, and HLA-B51, a class I MHC antigen, has been recognized as the strongest susceptibility factor for Behçet's disease. Despite the confirmation of the association of HLA-B51 with Behçet's disease in different populations, its pathogenic mechanisms remain elusive. HLA-B51 differs in only two amino acids from HLA-B52, other split antigen of HLA-B5, which is not associated with Behçet's disease. These two amino acids are located in the B pocket of the antigen-binding groove, which occupies the second amino acids of the bound peptides. To understand the nature of the HLA–peptide interactions, differences in structure and dynamics of two HLA alleles were investigated by molecular dynamics simulations using YAYDGKDYI, LPRSTVINI, and IPYQDLPHL peptides. For HLA-B51, all bound peptides fluctuated to larger extent than HLA-B52. Free energy profiles of unbinding process for YAYDGKDYI by steered molecular dynamics simulations showed that unbinding from HLA-B52 results in greater free energy differences than HLA-B51. These results suggest the possibility of an instability of HLA-B51 associated with the repertoire of peptides, and this finding may provide significant insight to its pathogenic role in Behçet's disease.

Original languageEnglish
Pages (from-to)644-658
Number of pages15
JournalChemical Biology and Drug Design
Volume96
Issue number1
DOIs
Publication statusPublished - 1 Jul 2020

Bibliographical note

Publisher Copyright:
© 2019 John Wiley & Sons A/S.

Funding

Mert Gur gratefully acknowledge the support of NVIDIA Corporation with the donation of the Titan V GPU used for this research. Mert Gur thankfully acknowledge the support of the Scientific Research Projects Unit (BAP) of the Istanbul Technical University.

FundersFunder number
Scientific Research Projects Unit
NVIDIA
British Association for Psychopharmacology
Istanbul Teknik Üniversitesi

    Keywords

    • Behçet's disease
    • free energy
    • HLA-B51
    • HLA-B52
    • molecular dynamics simulations
    • potential of mean force
    • steered molecular dynamics

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