title: Chronic Beryllium Disease: revealing the role of beryllium ion and small peptides binding to HLA-DP2.
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.
authors.affiliation: Computational Biophysics and Bioinformatics, Physics Department, Clemson University, Clemson, South Carolina, United States of America.
authors.forename: Marharyta
authors.initials: M
authors.lastname: Petukh
authors.affiliation: School of Nursing, Clemson University, Clemson, South Carolina, United States of America.
authors.forename: Bohua
authors.initials: B
authors.lastname: Wu
authors.affiliation: Computational Biophysics and Bioinformatics, Physics Department, Clemson University, Clemson, South Carolina, United States of America.
authors.forename: Shannon
authors.initials: S
authors.lastname: Stefl
authors.affiliation: Computational Biophysics and Bioinformatics, Physics Department, Clemson University, Clemson, South Carolina, United States of America.
authors.forename: Nick
authors.initials: N
authors.lastname: Smith
authors.affiliation: Department of Chemistry, Clemson University, Clemson, South Carolina, United States of America.
authors.forename: David
authors.initials: D
authors.lastname: Hyde-Volpe
authors.affiliation: Computational Biophysics and Bioinformatics, Physics Department, Clemson University, Clemson, South Carolina, United States of America.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.affiliation: Computational Biophysics and Bioinformatics, Physics Department, Clemson University, Clemson, South Carolina, United States of America.
authors.forename: Emil
authors.initials: E
authors.lastname: Alexov
mesh_terms: D001607:Berylliosis / Q000378:metabolism*; D001608:Beryllium / Q000378:metabolism*; D001665:Binding Sites; D002908:Chronic Disease; D059868:HLA-DP beta-Chains / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D062105:Molecular Docking Simulation; D010455:Peptides / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation
chemical_list: D059868:HLA-DP beta-Chains; C083176:HLA-DPw2 antigen; D010455:Peptides; D001608:Beryllium