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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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The pKa shift of two ionizable residues βGlu26 and βGlu69 on (A) HLA-DP2 binds to peptides (Four types as “natural”, “strong”, “weak” and “DR”, the same to the followings) (B) peptides bind to the complex (Be+protein) (C) (Be+peptides) complex binds to HLA-DP2 protein from pKa of native unbond protein.The pKa value was calculated as the average of 10 structures for each type of peptides.
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pone-0111604-g008: The pKa shift of two ionizable residues βGlu26 and βGlu69 on (A) HLA-DP2 binds to peptides (Four types as “natural”, “strong”, “weak” and “DR”, the same to the followings) (B) peptides bind to the complex (Be+protein) (C) (Be+peptides) complex binds to HLA-DP2 protein from pKa of native unbond protein.The pKa value was calculated as the average of 10 structures for each type of peptides.

Mentions: Binding frequently causes ionization changes, typically referred to as proton uptake/release [44], [45] and thus affects the electrostatic component of the binding free energy [46]. To investigate the effects of small peptides and the Be ion binding to HLA-DP2 on the ionization states of titratable groups, we carried out a pKa calculation using the MCCE program [41], [42], [43]. The pKa's of all ionizable residues of HLA-DP2 were calculated, and the protonation changes caused by the peptide binding, especially for the residues within the pocket, were analyzed. As described in the methods section, 120 structures were subjected to the pKa calculations. 40 of them were the HLA-DP2 bound with a peptide in the absence of the Be ion and 40 of them were the protein-Be complex bound to a small peptide and the rest were the protein bound to the Be-peptide complex. They were also divided into 4 groups by the peptide categories: “DR”, “natural”, “strong”, and “weak”. Also, for each group, we obtained the average pKa values of 10 structures along with the standard error and the calculated pKa shift of them from the native HLA-DP2 protein (PDB ID: 3LZM) (see Figure 8).


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)

The pKa shift of two ionizable residues βGlu26 and βGlu69 on (A) HLA-DP2 binds to peptides (Four types as “natural”, “strong”, “weak” and “DR”, the same to the followings) (B) peptides bind to the complex (Be+protein) (C) (Be+peptides) complex binds to HLA-DP2 protein from pKa of native unbond protein.The pKa value was calculated as the average of 10 structures for each type of peptides.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0111604-g008: The pKa shift of two ionizable residues βGlu26 and βGlu69 on (A) HLA-DP2 binds to peptides (Four types as “natural”, “strong”, “weak” and “DR”, the same to the followings) (B) peptides bind to the complex (Be+protein) (C) (Be+peptides) complex binds to HLA-DP2 protein from pKa of native unbond protein.The pKa value was calculated as the average of 10 structures for each type of peptides.
Mentions: Binding frequently causes ionization changes, typically referred to as proton uptake/release [44], [45] and thus affects the electrostatic component of the binding free energy [46]. To investigate the effects of small peptides and the Be ion binding to HLA-DP2 on the ionization states of titratable groups, we carried out a pKa calculation using the MCCE program [41], [42], [43]. The pKa's of all ionizable residues of HLA-DP2 were calculated, and the protonation changes caused by the peptide binding, especially for the residues within the pocket, were analyzed. As described in the methods section, 120 structures were subjected to the pKa calculations. 40 of them were the HLA-DP2 bound with a peptide in the absence of the Be ion and 40 of them were the protein-Be complex bound to a small peptide and the rest were the protein bound to the Be-peptide complex. They were also divided into 4 groups by the peptide categories: “DR”, “natural”, “strong”, and “weak”. Also, for each group, we obtained the average pKa values of 10 structures along with the standard error and the calculated pKa shift of them from the native HLA-DP2 protein (PDB ID: 3LZM) (see Figure 8).

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