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.

中文翻译：

---

分子动力学模拟为HLA-B51在Behçet疾病发病机理中的作用提供了分子见解。

白塞氏病是一种病因不明的炎性疾病。遗传倾向在其发病机理中起着重要作用，HLA-B51，I类MHC抗原，已被公认为是贝塞特氏病最强的易感性因子。尽管在不同人群中均证实了HLA-B51与Behçet病的相关性，但其致病机制仍然难以捉摸。HLA-B51与HLA-B5（HLA-B5的其他分裂抗原）仅两个氨基酸不同，后者与白塞氏病无关。这两个氨基酸位于抗原结合沟的B口袋中，占据结合肽段的第二个氨基酸。要了解HLA-肽相互作用的性质，通过使用YAYDGKDYI，LPRSTVINI和IPYQDLPHL肽的分子动力学模拟研究了两个HLA等位基因在结构和动力学上的差异。对于HLA-B51，所有结合的肽的波动幅度都大于HLA-B52。通过操纵分子动力学模拟，YAYDGKDYI解除结合过程的自由能谱显示，与HLA-B51相比，与HLA-B52的结合产生的自由能差异更大。这些结果表明与肽库有关的HLA-B51可能不稳定，这一发现可能为其在Behçet病中的致病作用提供重要见解。通过操纵分子动力学模拟，YAYDGKDYI的未结合过程的自由能谱显示，与HLA-B51相比，与HLA-B52的结合产生的自由能差异更大。这些结果表明与肽库有关的HLA-B51不稳定的可能性，这一发现可能为其在Behçet病中的致病作用提供重要见解。通过操纵分子动力学模拟，YAYDGKDYI的未结合过程的自由能谱显示，与HLA-B51相比，与HLA-B52的结合产生的自由能差异更大。这些结果表明与肽库有关的HLA-B51可能不稳定，这一发现可能为其在Behçet病中的致病作用提供重要见解。