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Chronic Beryllium Disease: revealing the role of beryllium ion and small peptides binding to HLA-DP2.

Petukh M, Wu B, Stefl S, Smith N, Hyde-Volpe D, Wang L, Alexov E - PLoS ONE (2014)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Computational Biophysics and Bioinformatics, Physics Department, Clemson University, Clemson, South Carolina, United States of America.

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.

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Related in: MedlinePlus

Graphical depiction of our investigation of the effects of the Be ion on the complex made up of a HLA-DP2 protein, the Be ion, and a small peptide.We investigated four types of small peptides (“Natural”, “Strong”, “Weak”, and “DR”) and two binding scenarios: (1) the ion bound to a small peptide and (2) the ion bound to the HLA-DP2 protein. Effect predictions include binding affinity, conformation changes of the peptide binding pocket, pKa shifts of titratable groups of the protein upon peptide and/or the Be ion binding.
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pone-0111604-g001: Graphical depiction of our investigation of the effects of the Be ion on the complex made up of a HLA-DP2 protein, the Be ion, and a small peptide.We investigated four types of small peptides (“Natural”, “Strong”, “Weak”, and “DR”) and two binding scenarios: (1) the ion bound to a small peptide and (2) the ion bound to the HLA-DP2 protein. Effect predictions include binding affinity, conformation changes of the peptide binding pocket, pKa shifts of titratable groups of the protein upon peptide and/or the Be ion binding.

Mentions: Although, in multiple papers the Be ion is suggested to bind directly to HLA-DP2 [27], [28], only recently it was experimentally shown [1] that Be binds first and then the peptide binds to the HLA-DR2-Be complex. However, the reason for this sequence of events is not clear and here we provide plausible explanation based on binding energy calculations. In addition, it is not clear if the sequence of the binding events causes different conformational changes of the HLA-DR2-Be-peptide complex. In this work, 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 thus 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. This is done by analyzing the changes in binding affinity and conformational changes of the protein upon binding the four sets of small peptides (Figure 1): peptides that are known to cause the activation of TC receptors in normal immune response; peptides that prefer to bind to HLA-DR but not HLA-DP; and peptides that are known to bind to the protein in the presence of the Be ion and induce the production of high/low concentration of inflammation cytokines in TCs that are the cause of the autoimmune disease [26]. It is anticipated that by comparing the effects of each set of peptides we will be able to reveal additional details of molecular mechanism of CBD along the finding of recent experimental work [1].


Chronic Beryllium Disease: revealing the role of beryllium ion and small peptides binding to HLA-DP2.

Petukh M, Wu B, Stefl S, Smith N, Hyde-Volpe D, Wang L, Alexov E - PLoS ONE (2014)

Graphical depiction of our investigation of the effects of the Be ion on the complex made up of a HLA-DP2 protein, the Be ion, and a small peptide.We investigated four types of small peptides (“Natural”, “Strong”, “Weak”, and “DR”) and two binding scenarios: (1) the ion bound to a small peptide and (2) the ion bound to the HLA-DP2 protein. Effect predictions include binding affinity, conformation changes of the peptide binding pocket, pKa shifts of titratable groups of the protein upon peptide and/or the Be ion binding.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4219729&req=5

pone-0111604-g001: Graphical depiction of our investigation of the effects of the Be ion on the complex made up of a HLA-DP2 protein, the Be ion, and a small peptide.We investigated four types of small peptides (“Natural”, “Strong”, “Weak”, and “DR”) and two binding scenarios: (1) the ion bound to a small peptide and (2) the ion bound to the HLA-DP2 protein. Effect predictions include binding affinity, conformation changes of the peptide binding pocket, pKa shifts of titratable groups of the protein upon peptide and/or the Be ion binding.
Mentions: Although, in multiple papers the Be ion is suggested to bind directly to HLA-DP2 [27], [28], only recently it was experimentally shown [1] that Be binds first and then the peptide binds to the HLA-DR2-Be complex. However, the reason for this sequence of events is not clear and here we provide plausible explanation based on binding energy calculations. In addition, it is not clear if the sequence of the binding events causes different conformational changes of the HLA-DR2-Be-peptide complex. In this work, 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 thus 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. This is done by analyzing the changes in binding affinity and conformational changes of the protein upon binding the four sets of small peptides (Figure 1): peptides that are known to cause the activation of TC receptors in normal immune response; peptides that prefer to bind to HLA-DR but not HLA-DP; and peptides that are known to bind to the protein in the presence of the Be ion and induce the production of high/low concentration of inflammation cytokines in TCs that are the cause of the autoimmune disease [26]. It is anticipated that by comparing the effects of each set of peptides we will be able to reveal additional details of molecular mechanism of CBD along the finding of recent experimental work [1].

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Computational Biophysics and Bioinformatics, Physics Department, Clemson University, Clemson, South Carolina, United States of America.

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.

Show MeSH
Related in: MedlinePlus