Our long-term goal is to enhance our understanding of metalloprotein structure, function and inhibition. The tools we will use are those of theoretical, computational and medicinal chemistry. The goal of this project is to understand, at the molecular-level, nickel homeostatis, regulation and the structure and function of nickel containing metalloproteins. In particular, we propose to study the catalytic mechanism, stability and inhibition of the ureases and through this understanding enhance our comprehension of enzyme catalysis, enzyme stability in extreme environments and the development of small-molecule therapeutics. The ureases are involved in a broad range of diseased states and a thorough understanding of the structure and function of this family of enzymes will impact our ability to modify the behavior of the ureases. The regulation of nickel ion import into a cell is governed by the nickel dependent transcription factor NikR, which represses the expression of the nickel membrane transporter nikABCDE in E. coli. We propose to develop a detailed understanding of the structure, function and dynamics of NikR, in order to gain insights into how nickel ion concentrations are regulated in cells. The primary enzymes that will be studied are the ureases from K. aerogenes, B. pasteurii and H. pylori and we will study the transcription factor NikR from E. coli. In the case of the ureases, the biological questions we are addressing is how do ureases catalyze the conversion of urea to ammonia and carbamate at a rate that is at least 10x14 times greater than the uncatalyzed reaction as well as how does the urease from H. pylori give this bacterium the ability to survive the low-pH conditions of the gut. In the case of NikR the biological question we are addressing is how toxic, yet necessary, metal ion concentrations are regulated in cells. With the aid of theoretical tools like quantum mechanics and molecular dynamics simulations we will study the uncatalyzed and the catalyzed decomposition of urea, the stability of H. pylori urease at low pH's and we will study the structure, function and dynamics of E. coli NikR. The insights obtained into these processes will have a major impact on human health through the understanding of urease catalysis and inhibition and via an enhanced understanding of the regulation of metal ions within cells.
Through the study of the enzyme urease and the metalloregulation protein NikR we will increase our understanding of how to control human ulcers formed by H. Pylori and we will increase our understanding of metal ion regulation in cells, whose dysfunction has an impact on human health through diseases like Alzheimer's and Lou Gehrig's disease.
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|Li, Pengfei; Merz Jr, Kenneth M (2017) Metal Ion Modeling Using Classical Mechanics. Chem Rev 117:1564-1686|
|Pan, Li-Li; Song, Lin Frank; Miao, Yipu et al. (2017) Mechanism of Formation of the Nonstandard Product in the Prenyltransferase Reaction of the G115T Mutant of FtmPT1: A Case of Reaction Dynamics Calling the Shots? Biochemistry 56:2995-3007|
|Yang, Y; Pan, L; Lightstone, F C et al. (2016) The Role of Molecular Dynamics Potential of Mean Force Calculations in the Investigation of Enzyme Catalysis. Methods Enzymol 577:1-29|
|Li, Pengfei; Song, Lin Frank; Merz Jr, Kenneth M (2015) Systematic Parameterization of Monovalent Ions Employing the Nonbonded Model. J Chem Theory Comput 11:1645-57|
|Minkara, Mona S; Weaver, Michael N; Merz Jr, Kenneth M (2015) Effect of 10.5 M Aqueous Urea on Helicobacter pylori Urease: A Molecular Dynamics Study. Biochemistry 54:4121-30|
|Macomber, Lee; Minkara, Mona S; Hausinger, Robert P et al. (2015) Reduction of urease activity by interaction with the flap covering the active site. J Chem Inf Model 55:354-61|
|Miao, Yipu; Merz Jr, Kenneth M (2015) Acceleration of High Angular Momentum Electron Repulsion Integrals and Integral Derivatives on Graphics Processing Units. J Chem Theory Comput 11:1449-62|
|Li, Pengfei; Song, Lin Frank; Merz Jr, Kenneth M (2015) Parameterization of highly charged metal ions using the 12-6-4 LJ-type nonbonded model in explicit water. J Phys Chem B 119:883-95|
|Chakravorty, Dhruva K; Merz Jr, Kenneth M (2014) Studying allosteric regulation in metal sensor proteins using computational methods. Adv Protein Chem Struct Biol 96:181-218|
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