Abstract
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.
Highlights
Chronic Beryllium Disease (CBD) is a pulmonary granulomatous disorder caused by an immune reaction when individuals are exposed to beryllium (Be) [2]
We investigate in silico both scenarios: (a) peptides which bind to the protein with the Be ion placed inside the protein pocket which induces conformational changes in HLA-DP2 that are necessary for its recognition by TCs; and (b) the Be ion binds to the peptide first and changes the peptide-binding specificity and affinity to HLA-DP2 resulting in conformational changes in the HLA-DP2 that are necessary for its recognition by TCs
In order to investigate the molecular mechanism of the HLA-DP2 malfunction in the presence of Be ions, we investigate two scenarios: peptideR(Be+protein) and (Be+peptide)Rprotein, along with the binding of four different sets of peptides (‘‘natural’’, ‘‘DR’’, ‘‘strong’’, and ‘‘weak’’, see Methods section for details)
Summary
Chronic Beryllium Disease (CBD) is a pulmonary granulomatous disorder caused by an immune reaction when individuals are exposed to beryllium (Be) [2]. About 18% of people who are exposed to Be in the workplace may develop CBD depending on a number of risk factors such as their genetic susceptibility, the duration, the concentration of the Be exposure, and their smoking habits [3,4,5,6,7]. Different conformational changes result in the activation of different TCs and lead to different immune responses These conformational changes are caused by the binding of variety of peptides to alleles of MHC II. The associations of MHC II alleles with various diseases have been previously reported [17,18,19]
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