Lindsay Zumwalt
Computational Investigation of the Mechanism of Cysteine Oxidation by Bleach (HOCl) in the Zinc-Binding Core of Cytosolic Chemoreceptor Transducer-Like Protein D (TlpD)
Overview: I investigated the chemical transformation that occurs when a conserved zinc-sulfur complex in Helicobacter pylori interacts with hypochlorite (bleach) secreted during gastric inflammation. My work provides the first detailed molecular-level understanding of how the bacteria efficiently colonizes the guts of >50% of the global population.Abstract: Helicobacter pylori, a gastric pathogen present in about 50% of the global population, is known to facilitate gastritis, stomach ulcers, and stomach cancer. Previous experimental studies show that local unfolding at the conserved chemoreceptor zinc-binding (CZB) domain within the transducer-like protein D (TlpD) cytoplasmic chemoreceptor upon contact with hypochlorite (a known biological oxidant), is implicated in the mode in which H. pylori effectively colonizes the stomach. However, the mechanism of oxidation at the conserved zinc-bound cysteine residue upon HOCl contact, the role of the zinc complex in modulating the reaction, and the origins of selective oxidation are unknown. Our work utilizes DFT computations to probe plausible mechanisms for the oxidation process, illuminates the role of ligand exchange equilibria at the zinc complex in modulating the reactivity and regioselectivity, and provides new hypotheses for the origin of the chemoattractant response. Insights from our computational study will be presented.
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