A multi-faceted research project is directly aimed at computational studies of enzymatic processes in aqueous solution. The theoretical approach centers on molecular dynamics simulations of enzymatic systems using combined quantum mechanical and molecular mechanical (QM/MM) methods. To achieve greater accuracy, we propose to further develop a mixed molecular orbital-valence bond (MOVB) method for simulation of enzyme reactions and sampling of the reaction pathway. In addition, we plan to implement a semi-empirical density functional theory for combined QM/MM calculations, which will significantly expand the scope of QM/MM applications to enzymatic systems, including metailoenzymes. A major thrust is to provide a deeper understanding of the remarkable catalytic power of enzymes. Our approach is to seek general catalytic principles, by examining individual enzymatic systems that share common features, but have different biological functions. In particular, the hydrolytic cysteine protease, human cathepsin K, and alanine and glutamate racemases, will be investigated in detail to understand substrate binding, reaction mechanism, and free energy profiles. Inhibitors of cathepsin K can reduce bone resorption, providing a promising therapeutic target for the treatment of osteoporosis and rheumatoid arthritis, while amino acid racemases are essential in the synthesis of the peptidoglycan layer of bacteria cell walls, rendering them attractive targets for inhibitors. The proposed computational study will provide insight into the mechanism of acid/base catalysis of these two important classes of enzymes. In addition, the dynamic conformational changes in thymidylate synthase (TS), that take place throughout the many-steps of the enzymatic reaction, will be studied. TS catalyzes the de novo synthesis of dTMP nucleotide for DNA synthesis, which has been extensively investigated experimentally. The proposed study will provide a deeper understanding of the roles of protein dynamic conformation change in the function of thymidylate synthase, and the results will be of general importance in enzyme catalysis. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM046736-12
Application #
6780331
Study Section
Molecular and Cellular Biophysics Study Section (BBCA)
Program Officer
Wehrle, Janna P
Project Start
1992-09-30
Project End
2008-03-31
Budget Start
2004-04-01
Budget End
2005-03-31
Support Year
12
Fiscal Year
2004
Total Cost
$268,746
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Dixit, Mudit; Weitman, Michal; Gao, Jiali et al. (2018) Comment on ""Substrate Folding Modes in Trichodiene Synthase: A Determinant of Chemo- and Stereoselectivity"". ACS Catal 8:1371-1375
Olson, Courtney M; Grofe, Adam; Huber, Christopher J et al. (2017) Enhanced vibrational solvatochromism and spectral diffusion by electron rich substituents on small molecule silanes. J Chem Phys 147:124302
Dixit, Mudit; Weitman, Michal; Gao, Jiali et al. (2017) Chemical Control in the Battle against Fidelity in Promiscuous Natural Product Biosynthesis: The Case of Trichodiene Synthase. ACS Catal 7:812-818
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Xue, Rui-Jie; Grofe, Adam; Yin, He et al. (2017) Perturbation Approach for Computing Infrared Spectra of the Local Mode of Probe Molecules. J Chem Theory Comput 13:191-201
Grofe, Adam; Chen, Xin; Liu, Wenjian et al. (2017) Spin-Multiplet Components and Energy Splittings by Multistate Density Functional Theory. J Phys Chem Lett 8:4838-4845
Ren, Haisheng; Provorse, Makenzie R; Bao, Peng et al. (2016) Multistate Density Functional Theory for Effective Diabatic Electronic Coupling. J Phys Chem Lett 7:2286-93
Gao, J (2016) Enzymatic Kinetic Isotope Effects from Path-Integral Free Energy Perturbation Theory. Methods Enzymol 577:359-88
Gao, Jiali; Grofe, Adam; Ren, Haisheng et al. (2016) Beyond Kohn-Sham Approximation: Hybrid Multistate Wave Function and Density Functional Theory. J Phys Chem Lett 7:5143-5149
Wang, Yingjie; Gao, Jiali (2015) Projected hybrid orbitals: a general QM/MM method. J Phys Chem B 119:1213-24

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