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Molecular Dynamics Study of Helicobacter pylori Urease.

Minkara MS, Ucisik MN, Weaver MN, Merz KM - J Chem Theory Comput (2014)

Bottom Line: Chem.An additional flap in the active site was elaborated upon that we postulate may serve as an exit conduit for hydrolysis products.Finally we discuss the internal hollow cavity and present analysis of the distribution of sodium ions over the course of the simulation.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Quantum Theory Project, 2328 New Physics Building, University of Florida , Gainesville, Florida 32611-8435, United States.

ABSTRACT
Helicobacter pylori have been implicated in an array of gastrointestinal disorders including, but not limited to, gastric and duodenal ulcers and adenocarcinoma. This bacterium utilizes an enzyme, urease, to produce copious amounts of ammonia through urea hydrolysis in order to survive the harsh acidic conditions of the stomach. Molecular dynamics (MD) studies on the H. pylori urease enzyme have been employed in order to study structural features of this enzyme that may shed light on the hydrolysis mechanism. A total of 400 ns of MD simulation time were collected and analyzed in this study. A wide-open flap state previously observed in MD simulations on Klebsiella aerogenes [Roberts et al. J. Am. Chem. Soc. 2012, 134, 9934] urease has been identified in the H. pylori enzyme that has yet to be experimentally observed. Critical distances between residues on the flap, contact points in the closed state, and the separation between the active site Ni(2+) ions and the critical histidine α322 residue were used to characterize flap motion. An additional flap in the active site was elaborated upon that we postulate may serve as an exit conduit for hydrolysis products. Finally we discuss the internal hollow cavity and present analysis of the distribution of sodium ions over the course of the simulation.

No MeSH data available.


Related in: MedlinePlus

RMSD (Ångstroms) ofthe entire H. pylori urease structure (purple), andthe closed (blue), semiopen (red), and wide-open (green) flap states.
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fig3: RMSD (Ångstroms) ofthe entire H. pylori urease structure (purple), andthe closed (blue), semiopen (red), and wide-open (green) flap states.

Mentions: The root-mean-squaredeviation (RMSD, Figure 3) was obtained forthe entire structure and of eachflap individually using the first frame after equilibration as thereference point. The RMSD of the entire structure levels off approximately250 ns into the simulation at a value of approximately 2.5 Å.For the flap that remains closed (flap 1), the maximum RMSD foundover time was 1.87 Å and overall this flap undergoes only modestfluctuation. For the semiopen flap state displayed in Figure 3 (flap 5), the maximum observed RMSD is approximately3 Å; Flap 5 was observed to have an RMSD that did not vary appreciablyfrom 2.6 Å after 150 ns. In the wide-open flap (flap 11) theRMSD reaches 5.25 Å and after two-thirds of the simulation remainsaround 3.8 Å before dipping slightly over the final 50 ns, althoughat a value well above the total simulation RMSD. Further RMSD plotsfor the remaining flaps are provided in the SupportingInformation (SI) (Figures S5–S7).


Molecular Dynamics Study of Helicobacter pylori Urease.

Minkara MS, Ucisik MN, Weaver MN, Merz KM - J Chem Theory Comput (2014)

RMSD (Ångstroms) ofthe entire H. pylori urease structure (purple), andthe closed (blue), semiopen (red), and wide-open (green) flap states.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4020587&req=5

fig3: RMSD (Ångstroms) ofthe entire H. pylori urease structure (purple), andthe closed (blue), semiopen (red), and wide-open (green) flap states.
Mentions: The root-mean-squaredeviation (RMSD, Figure 3) was obtained forthe entire structure and of eachflap individually using the first frame after equilibration as thereference point. The RMSD of the entire structure levels off approximately250 ns into the simulation at a value of approximately 2.5 Å.For the flap that remains closed (flap 1), the maximum RMSD foundover time was 1.87 Å and overall this flap undergoes only modestfluctuation. For the semiopen flap state displayed in Figure 3 (flap 5), the maximum observed RMSD is approximately3 Å; Flap 5 was observed to have an RMSD that did not vary appreciablyfrom 2.6 Å after 150 ns. In the wide-open flap (flap 11) theRMSD reaches 5.25 Å and after two-thirds of the simulation remainsaround 3.8 Å before dipping slightly over the final 50 ns, althoughat a value well above the total simulation RMSD. Further RMSD plotsfor the remaining flaps are provided in the SupportingInformation (SI) (Figures S5–S7).

Bottom Line: Chem.An additional flap in the active site was elaborated upon that we postulate may serve as an exit conduit for hydrolysis products.Finally we discuss the internal hollow cavity and present analysis of the distribution of sodium ions over the course of the simulation.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Quantum Theory Project, 2328 New Physics Building, University of Florida , Gainesville, Florida 32611-8435, United States.

ABSTRACT
Helicobacter pylori have been implicated in an array of gastrointestinal disorders including, but not limited to, gastric and duodenal ulcers and adenocarcinoma. This bacterium utilizes an enzyme, urease, to produce copious amounts of ammonia through urea hydrolysis in order to survive the harsh acidic conditions of the stomach. Molecular dynamics (MD) studies on the H. pylori urease enzyme have been employed in order to study structural features of this enzyme that may shed light on the hydrolysis mechanism. A total of 400 ns of MD simulation time were collected and analyzed in this study. A wide-open flap state previously observed in MD simulations on Klebsiella aerogenes [Roberts et al. J. Am. Chem. Soc. 2012, 134, 9934] urease has been identified in the H. pylori enzyme that has yet to be experimentally observed. Critical distances between residues on the flap, contact points in the closed state, and the separation between the active site Ni(2+) ions and the critical histidine α322 residue were used to characterize flap motion. An additional flap in the active site was elaborated upon that we postulate may serve as an exit conduit for hydrolysis products. Finally we discuss the internal hollow cavity and present analysis of the distribution of sodium ions over the course of the simulation.

No MeSH data available.


Related in: MedlinePlus