Molecular Dynamics Simulation Reveals the Selective Binding of Human Leukocyte Antigen Alleles Associated with Behçet's Disease

<div><p>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.</p></div

Hydrogen bond interactions.

<p>The percentage occupancy of H-bonds averaged over the last 25 ns of simulation time between the nine residues (P1–P9) of the MICA-TM peptide and the HLA residues for the four complexes.</p

Decomposition energy per HLA residue fingerprint plots.

<p>The HLA contribution to the MICA-TM binding is shown in terms of the electrostatic (ele) and van der Waals (vdW) interactions.</p

Structural basis of HLA class I.

<p>(A) Schematic model of HLA buried in the transmembrane. (B) HLA (pink) contains the <i>α</i>1 and <i>α</i>2 subdomains that contribute to the peptide binding groove, while <i>α</i>3 is the C-terminal domain in complex with <i>ß</i>₂-microgluobulin (<i>ß</i>₂m) as a noncovalently supported protein (cyan). (C) Ribbon and (D) van der Waals surface representations of the MICA-TM nonapeptide (green stick model) occupied in the peptide binding sub-sites (S1–S9, shaded by different colors) of HLA-B*51:01.</p

Averaged decomposition energy contributions in HLA binding to MICA-TM.

<p>Per-residue decomposition energies and the energy components in terms of the electrostatic (ele) and van der Waals (vdW) interactions for the P1–P9 residues of MICA-TM.</p

The binding free energy and energy components (kcal/mol) for the four HLA/MICA-TM complexes predicted by the MM/PBSA method.

<p>HLA alleles are</p><p>^<i>a</i> associated or</p><p>^<i>b</i> not associated with Behçet’s disease (BD).</p><p>Data are shown as the mean ± SD, derived from independent simulations. Means within a paired row (HLA-A or HLA-B alleles that are associated with BD versus that are not) followed by a different letter are significantly different.</p><p>Δ<i>G</i>_<i>bind</i> is the binding energy with inclusion of entropic term.</p><p>The binding free energy and energy components (kcal/mol) for the four HLA/MICA-TM complexes predicted by the MM/PBSA method.</p

Structural flexibilities of the HLA alleles bound with the MICA-TM peptide.

<p>Structural flexibilities were evaluated by B-factor. The ribbon color changes from blue (rigid) to red (flexible) to represent a low to high protein flexibility. Note that for clarity only the binding groove structure and the MICA-TM peptide are shown.</p