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

Autor:	Burak Erman, Ahmet Gül, Mert Golcuk, Mert Gur
Rok vydání:	2020
Předmět:	Protein Conformation Behcet's disease Disease Human leukocyte antigen Molecular Dynamics Simulation Biology 01 natural sciences Biochemistry Pathogenesis Molecular dynamics Antigen Drug Discovery medicine Humans Amino Acid Sequence Allele Alleles Pharmacology chemistry.chemical_classification Genetics 010405 organic chemistry Behcet Syndrome Organic Chemistry medicine.disease eye diseases 0104 chemical sciences Amino acid stomatognathic diseases 010404 medicinal & biomolecular chemistry chemistry HLA-B51 Antigen Thermodynamics Molecular Medicine HLA-B52 Antigen Peptides Protein Binding
Zdroj:	Chemical Biology & Drug Design. 96:644-658
ISSN:	1747-0285 1747-0277
DOI:	10.1111/cbdd.13658
Popis:	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.
Databáze:	OpenAIRE
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