NDLI: Dynamical insights into the differential characteristics of Mycobacterium avium subsp. paratuberculosis peptide binding to HLA-DRB1 proteins associated with multiple sclerosis

Content Provider	Royal Society of Chemistry (RSC)
Author	Sechi, Leonardo A. Pieroni, Enrico Marrosu, Maria Giovanna Kumar, Amit Caboni, Pierluigi Atzori, Luigi
Copyright Year	2015
Abstract	Mycobacterium avium subsp. paratuberculosis (MAP) infections have been recently linked to multiple sclerosis in Sardinian population, with an amino acid sequence 301–309 of MAP2694 protein possessing a high antigenic potential. Peptide presentation by HLA protein is an important step in adaptive immune response to pathogens, which is linked to the stable peptide–HLA complex. In this study we focus on two predisposing (15:01, 03:01) and two protective (16:01, 15:02) HLA-DRB1 proteins in Sardinian population. We investigate in detail their binding characteristics to the MAP2694-derived peptide, with the aim of linking disease susceptibility to protein structural-dynamical features and ultimately to molecular mechanisms contributing to the disease. Using dihedral angle principal component analysis, we observe distinct chemical configurations and dynamics of the HLA peptide binding, between the predisposing and protective proteins upon binding. The difference persists in the collective motion of residues near the amino-terminal region of the peptide-binding groove involving polymorphic HLA-DRB1 residue 86. Buried surface area and binding energy estimations also support the protein distinction, suggesting preferential peptide binding towards the predisposing proteins. Finally, water dynamics analysis in the binding groove highlighted the role of slow water molecules in bridging H-bond interactions between the protein and peptide residues. Our work demonstrates the ability of molecular simulations to characterize MAP peptide binding to the proteins associated with multiple sclerosis in Sardinian population. Overall, this distinction between the predisposing and protective proteins can be associated with a biological mechanism that functionally contributes to disease onset in predisposed individuals.
Starting Page	1355
Ending Page	1366
Page Count	12
File Format	HTM / HTML PDF
ISSN	11440546
Volume Number	39
Issue Number	2
Journal	New Journal of Chemistry
DOI	10.1039/c4nj01903b
Language	English
Publisher	Royal Society of Chemistry
Access Restriction	Open
Subject Keyword	Dihedral angle Multiple sclerosis Sardinian people Paratuberculosis Protein Adaptive immune system Slow Water Mycobacterium avium-intracellulare infection Carboxylic acid Human leukocyte antigen Binding energy Peptide HLA-DRB1 Principal component analysis
Content Type	Text
Resource Type	Article
Subject	Chemistry Materials Chemistry Catalysis

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