TY - JOUR
T1 - Molecular mechanism of Be2+-ion binding to HLA-DP2
T2 - Tetrahedral coordination, conformational changes and multi-ion binding
AU - De, Susmita
AU - Sabu, Gopika
AU - Zacharias, Martin
N1 - Publisher Copyright:
© 2020 the Owner Societies.
PY - 2020
Y1 - 2020
N2 - 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 the human leukocyte antigen protein (HLA-DP2) and peptide (M2) results in favorable interaction with the 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 a HLA-DP2 protein and M2 peptide. The interaction between the 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 the M2 peptide. This multi-ion cavity consists of tetrahedrally coordinated static Be2+ and Na+-ions, as well as one dynamically exchangeable Na+-ion. The smaller size and higher charge of the Be2+-ion as compared to the Na+-ion reduce the distance between the M2 peptide and the β-chain of HLA-DP2, which results in conformational change suitable for TCR binding. However, the replacement of the Be2+ by the Na+-ion could not generate a suitable binding site for TCR.
AB - 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 the human leukocyte antigen protein (HLA-DP2) and peptide (M2) results in favorable interaction with the 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 a HLA-DP2 protein and M2 peptide. The interaction between the 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 the M2 peptide. This multi-ion cavity consists of tetrahedrally coordinated static Be2+ and Na+-ions, as well as one dynamically exchangeable Na+-ion. The smaller size and higher charge of the Be2+-ion as compared to the Na+-ion reduce the distance between the M2 peptide and the β-chain of HLA-DP2, which results in conformational change suitable for TCR binding. However, the replacement of the Be2+ by the Na+-ion could not generate a suitable binding site for TCR.
UR - http://www.scopus.com/inward/record.url?scp=85077402124&partnerID=8YFLogxK
U2 - 10.1039/c9cp05695e
DO - 10.1039/c9cp05695e
M3 - Article
C2 - 31833509
AN - SCOPUS:85077402124
SN - 1463-9076
VL - 22
SP - 799
EP - 810
JO - Physical Chemistry Chemical Physics
JF - Physical Chemistry Chemical Physics
IS - 2
ER -