Molecular Mechanism of Be2+-Ion Binding to HLA-DP2: Tetrahedral Coordination, Conformational Changes and Multi-ion Binding
The chemistry of beryllium is rather unusual, however, less explored as compared to other main group elements. This is mainly attributed to the high toxicity of beryllium leading to chronic granulomatous pneumonitis, called chronic beryllium disease (CBD). It has been reported that Be2+-ion binding to human leukocyte antigen protein (HLA-DP2) and peptide (M2) results in favorable interaction with T-cell receptor protein (TCR), which initiates immune-mediated toxicity. We have carried out molecular dynamics (MD) simulations combined with quantum mechanical/molecular mechanical (QM/MM) studies to explore the binding nature of Be2+ with HLA-DP2 protein and M2 peptide. The interaction between negatively charged M2 peptide and the negatively charged binding cleft of HLA-DP2 is unfavorable. However, this interaction is stabilized by one Be2+ and two Na+-ions bridged by negatively charged carboxyl groups of glutamate residues (β26E and β69E) of the β-chain of HLA-DP2 and one glutamate (p7E) and one aspartate residue (p4D) of M2 peptide. This multi-ion cavity consists of tetrahedrally coordinated static Be2+ and Na+-ion as well as one dynamically exchangeable Na+-ion. The smaller size and higher charge of Be2+-ion as compared to Na+-ion reduce the distance between M2 peptide and β-chain of HLA-DP2, which results in conformational change suitable for TCR binding. However, replacement of Be2+ by Na+-ion could not generate suitable binding site for TCR.