A multi-faceted research project is directed aimed at computational studies of enzymatic processes in aqueous solution. The theoretical approach centers on molecular dynamics free energy simulations of enzymes, making use of combined quantum mechanical and molecular mechanical (QM/MM) methods. A major goal is to increase the capability of QM/MM methods and to achieve greater accuracy than conventional approaches. We propose to further improve the mixed molecular orbital and valence bond (MOVB) theory, coupled with the self-consistent charge tight-bonding density functional theory (SCC-DFTB) and extension to the CHARMM program with ab initio and DFT methods, such that the theoretical model can be conveniently calibrated, tested and used by experimental biochemists as a research tool to help interpret experiment findings. The MOVB method has been developed at theoretical levels that include ab initio and semiempirical molecular orbital and density functional theory. One goal of the present study is to incorporate the procedure into molecular dynamics simulation programs for effectively modeling enzymatic reactions. A major thrust of this project is to provide a deeper understanding of the underlying principles and mechanisms of enzymatic reactions. During this grant period, we focus on the catalytic mechanism of histone lysine demethylases with emphasis on the Jumonji C domain containing enzymes, which belong to a large class of enzymes that utilize a non-heme high- valent iron-oxo intermediate. Histone lysine demethylases along with other histone protein modifying enzymes play a critical role in epigenetic regulation and have been found to be associated with cancer development and progress. In addition, we seek to address the general properties of enzymatic proton-coupled electron transfer reactions and the effects of protein dynamics and enzyme reorganization energies on these processes. The MOVB method provides an important research tool to study these questions, and the results will be of general importance to protein engineering and inhibitor design. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page

Public Health Relevance

Proteins are workhorses in the living cell, performing all the fundamental tasks from metabolism to cell growth. An important goal is to develop pharmaceutical drugs against protein targets that are responsible for cancer growth and other diseases. The research described in this proposal aims at the fundamental understanding of the mechanism and function of enzymes, proteins that catalyze chemical reactions and bioenergy transformation, and the knowledge gained from these studies can help design inhibitors and engineer specialized proteins for biomedical and industrial applications. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Macromolecular Structure and Function D Study Section (MSFD)
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Preusch, Peter
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University of Minnesota Twin Cities
Schools of Arts and Sciences
United States
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Mazack, Michael J M; Gao, Jiali (2014) Quantum mechanical force field for hydrogen fluoride with explicit electronic polarization. J Chem Phys 140:204501
Cembran, Alessandro; Kim, Jonggul; Gao, Jiali et al. (2014) NMR mapping of protein conformational landscapes using coordinated behavior of chemical shifts upon ligand binding. Phys Chem Chem Phys 16:6508-18
Fan, Yao; Cembran, Alessandro; Ma, Shuhua et al. (2013) Connecting protein conformational dynamics with catalytic function as illustrated in dihydrofolate reductase. Biochemistry 52:2036-49
Rajamani, Ramkumar; Lin, Yen-Lin; Gao, Jiali (2011) The opsin shift and mechanism of spectral tuning in rhodopsin. J Comput Chem 32:854-65
Perlmutter, Jason D; Drasler 2nd, William J; Xie, Wangshen et al. (2011) All-atom and coarse-grained molecular dynamics simulations of a membrane protein stabilizing polymer. Langmuir 27:10523-37
Grimes, Shelley; Ma, Shuhua; Gao, Jiali et al. (2011) Role of ?29 connector channel loops in late-stage DNA packaging. J Mol Biol 410:50-9
Lin, Yen-lin; Gao, Jiali (2011) Kinetic isotope effects of L-Dopa decarboxylase. J Am Chem Soc 133:4398-403
Wong, Kin-Yiu; Gao, Jiali (2011) Insight into the phosphodiesterase mechanism from combined QM/MM free energy simulations. FEBS J 278:2579-95
Lin, Yen-lin; Gao, Jiali (2010) Internal proton transfer in the external pyridoxal 5'-phosphate Schiff base in dopa decarboxylase. Biochemistry 49:84-94
Cembran, Alessandro; Payaka, Apirak; Lin, Yen-Lin et al. (2010) A Non-Orthogonal Block-Localized Effective Hamiltonian Approach for Chemical and Enzymatic Reactions. J Chem Theory Comput 6:2242-2251

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