Molecular Dynamics Simulation Reveals the Selective Binding of Human Leukocyte Antigen Alleles Associated with Behçet's Disease.
Behçet's disease (BD), a multi-organ inflammatory disorder, is associated with the presence of the human leukocyte antigen (HLA) HLA-B*51 allele in many ethnic groups. The possible antigen involvement of the major histocompatibility complex class I chain related gene A transmembrane (MICA-TM) nonapeptide (AAAAAIFVI) has been reported in BD symptomatic patients. This peptide has also been detected in HLA-A*26:01 positive patients. To investigate the link of BD with these two specific HLA alleles, molecular dynamics (MD) simulations were applied on the MICA-TM nonapeptide binding to the two BD-associated HLA alleles in comparison with the two non-BD-associated HLA alleles (B*35:01 and A*11:01). The MD simulations were applied on the four HLA/MICA-TM peptide complexes in aqueous solution. As a result, stabilization for the incoming MICA-TM was found to be predominantly contributed from van der Waals interactions. The P2/P3 residue close to the N-terminal and the P9 residue at the C-terminal of the MICA-TM nonapeptide served as the anchor for the peptide accommodated at the binding groove of the BD associated HLAs. The MM/PBSA free energy calculation predicted a stronger binding of the HLA/peptide complexes for the BD-associated HLA alleles than for the non-BD-associated ones, with a ranked binding strength of B*51:01 > B*35:01 and A*26:01 > A*11:01. Thus, the HLAs associated with BD pathogenesis expose the binding efficiency with the MICA-TM nonapeptide tighter than the non-associated HLA alleles. In addition, the residues 70, 73, 99, 146, 147 and 159 of the two BD-associated HLAs provided the conserved interaction for the MICA-TM peptide binding.
Program in Biotechnology, Faculty of Science, Chulalongkorn University, Bangkok, Thailand.
Sirilak
S
Kongkaew
Department of Chemistry, Faculty of Science, Ramkhamhaeng University, Bangkok, Thailand.
Pathumwadee
P
Yotmanee
Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok, Thailand; Ph.D. Program in Bioinformatics and Computational Biology, Faculty of Science, Chulalongkorn University, Bangkok, Thailand.
Thanyada
T
Rungrotmongkol
Computational Chemistry Unit Cell, Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok, Thailand.
Nopporn
N
Kaiyawet
Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok, Thailand.
Arthitaya
A
Meeprasert
Department of Ophthalmology, University of Tokyo, Tokyo, Japan.
Toshikatsu
T
Kaburaki
School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.
Hiroshi
H
Noguchi
Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Tokyo, Japan.
Fujio
F
Takeuchi
Department of Chemistry, Faculty of Science, Chiang Mai University, Chiang Mai, Thailand.
Nawee
N
Kungwan
Computational Chemistry Unit Cell, Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok, Thailand.
Supot
S
Hannongbua
D000483:Alleles; D000595:Amino Acid Sequence; D001528:Behcet Syndrome / Q000235:genetics / Q000276:immunology*; D015234:HLA-A Antigens / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D059949:HLA-B51 Antigen / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000737:chemistry / Q000276:immunology*; D006801:Humans; D056004:Molecular Dynamics Simulation
D015234:HLA-A Antigens; C541137:HLA-A*26:01 antigen; D059949:HLA-B51 Antigen; D015395:Histocompatibility Antigens Class I; C099187:MHC class I-related chain A