Chronic
Beryllium (Be) Disease (CBD) is a granulomatous disorder that predominantly affects the lung. The CBD is caused by Be exposure of individuals carrying the
HLA-DP2 protein of the major histocompatibility complex class II (MHCII). While the involvement of Be in the development of CBD is obvious and the binding site and the sequence of Be and
peptide binding were recently experimentally revealed [1], the interplay between induced conformational changes and the changes of the
peptide binding affinity in presence of Be were not investigated. Here we carry out in silico modeling and predict the Be binding to be within the acidic pocket (Glu26, Glu68 and Glu69) present on the
HLA-DP2 protein in accordance with the experimental work [1]. In addition, the modeling indicates that the Be ion binds to the
HLA-DP2 before the corresponding
peptide is able to bind to it. Further analysis of the MD generated trajectories reveals that in the presence of the Be ion in the binding pocket of
HLA-DP2, all the different types of
peptides induce very similar conformational changes, but their binding affinities are quite different. Since these conformational changes are distinctly different from the changes caused by
peptides normally found in the cell in the absence of Be, it can be speculated that CBD can be caused by any
peptide in presence of Be ion. However, the affinities of
peptides for Be loaded
HLA-DP2 were found to depend of their
amino acid composition and the
peptides carrying acidic group at positions 4 and 7 are among the strongest binders. Thus, it is proposed that CBD is caused by the exposure of Be of an individual carrying the
HLA-DP2*0201 allele and that the binding of Be to
HLA-DP2 protein alters the conformational and ionization properties of
HLA-DP2 such that the binding of a
peptide triggers a wrong signaling cascade.