The goal of the proposed research is to develop and apply theoretical simulation techniques to study the nature and energetics of protein- substrate and protein-inhibitor interactions, the mechanisms of uncatalyzed solution phase reactions, and enzymatically catalyzed reactions. Theoretical insights into these phenomenon will have a major impact on human health. The increase in our understanding of existing inhibitors and the design of new enzyme inhibitors will have a major impact on improving the human condition. An increase in our knowledge of protein structure and function will have a major impact on biotechnology, because it will allow for the ab initio design of new proteins with increased or more selective catalytic properties. To address these issues we have decided to focus on one protein and subject to intense theoretical scrutiny. Our model will be the zinc metalloenzyme human carbonic anhydrase II (HCAII), which is of great biomedical importance because of its role in physiological processes involving CO2, and because inhibitors of this enzyme are drugs used in the treatment of glaucoma. Our first goal will be to develop the necessary molecular mechanical potential function parameters for the catalytically necessary zinc ion in this enzyme, followed by the development of a coupled quantum mechanical/molecular mechanical simulation package, which will be used to study both the uncatalyzed and catalyzed reactions of CO2. In order to identify what structural features are important for enzymatic catalysis it is first useful to understand the uncatalyzed gas-phase and solution phase reactions. Thus, we will initiate theoretical studies to examine the uncatalyzed solution and gas-phase reaction of CO2 with hydroxide, which will allow for insights into how HCAII catalyzes this reaction. The remainder of the proposed studies include investigations on the solution and gas-phase reaction of CO2 with water, which is an important reaction in the buffering of blood, studies on the catalytic mechanism of HCAII, studies on HCAII-substrate interactions, and a through scrutiny of known and potentially new HCAII inhibitors.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29GM044974-04
Application #
2182901
Study Section
Molecular and Cellular Biophysics Study Section (BBCA)
Project Start
1991-04-01
Project End
1996-03-31
Budget Start
1994-04-01
Budget End
1995-03-31
Support Year
4
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Pennsylvania State University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
City
University Park
State
PA
Country
United States
Zip Code
16802
Chakravorty, Dhruva K; Li, Pengfei; Tran, Trang T et al. (2016) Metal Ion Capture Mechanism of a Copper Metallochaperone. Biochemistry 55:501-9
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
Ucisik, Melek N; Chakravorty, Dhruva K; Merz Jr, Kenneth M (2015) Models for the Metal Transfer Complex of the N-Terminal Region of CusB and CusF. Biochemistry 54:4226-35
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
Faver, John C; Merz Jr, Kenneth M (2014) Fragment-based error estimation in biomolecular modeling. Drug Discov Today 19:45-50
Pan, Li-Li; Yang, Yue; Merz Jr, Kenneth M (2014) Origin of product selectivity in a prenyl transfer reaction from the same intermediate: exploration of multiple FtmPT1-catalyzed prenyl transfer pathways. Biochemistry 53:6126-38
Chakravorty, Dhruva K; Wang, Bing; Lee, Chul Won et al. (2013) Solution NMR refinement of a metal ion bound protein using metal ion inclusive restrained molecular dynamics methods. J Biomol NMR 56:125-37
Chakravorty, Dhruva K; Parker, Trent M; Guerra, Alfredo J et al. (2013) Energetics of zinc-mediated interactions in the allosteric pathways of metal sensor proteins. J Am Chem Soc 135:30-3
Ucisik, Melek N; Chakravorty, Dhruva K; Merz Jr, Kenneth M (2013) Structure and dynamics of the N-terminal domain of the Cu(I) binding protein CusB. Biochemistry 52:6911-23
Zheng, Zheng; Merz Jr, Kenneth M (2013) Development of the knowledge-based and empirical combined scoring algorithm (KECSA) to score protein-ligand interactions. J Chem Inf Model 53:1073-83

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