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 enzymatic reactions using combined quantum mechanical and molecular mechanical (QM/MM methods. To achieve greater accuracy and capability, we propose to further improve the mixed molecular orbital and valence bond (MOVB) theory such that it can be conveniently calibrated, validated and used by biochemists as a computational tool to help interpret experiment findings. The MOVB theory will be implemented and distributed with the capability of using ab initio and semiempirical molecular orbital and density functional theory. In addition, we plan to incorporate explicit polarization effects into combined QM/MM calculations, which can significantly increase the accuracy to describe enzyme and substrate interactions consistently. A major thrust is to provide a deeper understanding of the underlying principles and mechanisms of enzymatic reactions. During this grant period, we aim to elucidate the origin of catalysis in histone lysine demethylases, which catalyze the same chemical transformation by different mechanisms and using different enzyme cofactors. On the other hand, studies of the L-dopa decarboxylase, an enzyme related to the treatment of Parkinson's disease, can provide insight into chemical selectivity by different enzymes employing the pyridoxal phosphate cofactor. Histone lysine demethylases are two classes of enzymes recently discovered to dynamically control the methylation states of chromatin, which are related to gene activation and gene silencing and these enzymes are potential targets for anticancer drugs. In addition, we seek to address the effects of protein dynamics and enzyme reorganization energies on catalysis. 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.

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 the knowledge gained from these studies can help design inhibitors and engineer specialized proteins for biomedical and industrial applications.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-BCMB-B (02))
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Preusch, Peter C
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University of Minnesota Twin Cities
Schools of Arts and Sciences
United States
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Grofe, Adam; Qu, Zexing; Truhlar, Donald G et al. (2017) Diabatic-At-Construction Method for Diabatic and Adiabatic Ground and Excited States Based on Multistate Density Functional Theory. J Chem Theory Comput 13:1176-1187
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
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
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
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
Sun, Weichao; Shao, Mengyao; Ren, Haisheng et al. (2015) A New Type of Electron Relay Station in Proteins: Three-Piece S:??S?S??:S Resonance Structure. J Phys Chem C Nanomater Interfaces 119:6998-7005
Wang, Yingjie; Gao, Jiali (2015) Projected hybrid orbitals: a general QM/MM method. J Phys Chem B 119:1213-24
Kim, Jonggul; Masterson, Larry R; Cembran, Alessandro et al. (2015) Dysfunctional conformational dynamics of protein kinase A induced by a lethal mutant of phospholamban hinder phosphorylation. Proc Natl Acad Sci U S A 112:3716-21

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