Mechanism of Urea Conduction through H. Pylori UreI

Abstract

The carcinogenic bacterium Helicobacter Pylori is found within the stomach of over 75% of the human population, and directly contributes to ailments such as gastritis, stomach ulcers, and stomach cancer. This neutrophile relies on the cytoplasmic hydrolysis of gastric urea into ammonia, which buffers the bacteria from the acidic environment. Urea uptake is a crucial mechanism of survival, and the protein HpUreI regulates and enhances this process. HpUreI is part of the urease operon in many bacteria. There are 7 genes in the urease operon, 2 of which are structural proteins, and 5 of which are accessory proteins. All of these proteins contribute directly to H. Pylori thriving in a low pH environment. The buffering action of the converted urea into ammonia and carbon dioxide boosts the local pH to 5.5 near the membrane. The structure of HpUreI protein shows two constriction sites in all six pores that allow water and urea to pass into the cytoplasm. This study reports results from various Molecular Dynamics simulations, including a high-concentration equilibration model saturated with urea, a steered molecular dynamics (SMD) simulation directing six ligands through each segment of the hexameric structure, and umbrella sampling simulations through the length of the pore. We report the energy profile identifying specific points of constriction and binding with both the ligand and free water saturating the structure.