Structure and dynamics of outer membrane lectin involved in the surface expression of Group 1 capsular polysaccharides

Nair, S A (2014) Structure and dynamics of outer membrane lectin involved in the surface expression of Group 1 capsular polysaccharides. Masters thesis, Indian Institute of Technology, Hyderabad.

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Abstract

Multi-drug resistance of Gram-negative bacteria such as Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter baumanii is the major cause for human mortality worldwide. Bacterial capsular polysaccharides (CPS) are important virulence determinants of such Gram-negative bacteria, helping in colonization and offering antibacterial drug resistance. Though the outer membrane protein Wzi has been identified as responsible for surface anchorage of the Group 1 capsule of E. coli, the mechanism involved remains unknown. In this context, we carry out molecular dynamics simulations of Wzi protein and its mutants. Our results for the first time reveal, the water conducting property of Wzi protein. Two residues, namely Tyr380 and Trp39 at the extracellular and periplasmic faces respectively are identified to play an important role in regulating water conduction. A potassium ion binding pocket is observed on the extracellular face of the protein, coinciding with the water entry region. We hypothesize that this may be the interacting region for CPS onto the bacterial surface through non-covalent interactions. We also model the extracellular loop L5, which is absent in the crystal structure. Simulations show that it plays a major role in anchoring the protein to the lipid membrane. In addition, a hexameric repeating unit of Group 1 capsular polysaccharide, →2)-α-D-Manp-(1→3)-β-D-Galp-(1→ chain carrying a β-D-GlcUAp-(1→3)-α-D-Galp-(1→ branch at position 3 of the mannose is also be simulated and is found to exist in two major conformations, namely bent and extended. The outcome of this study may facilitate the design of antibacterial drugs that can specifically alter the water conductance of Wzi. This may further perturb CPS binding to the bacterial surface and thus lead to decreased virulence and higher antibiotic susceptibility.

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