Based on structural information from X-ray and NMR experiments, computational simulations performed us- ing molecular dynamics and the quantum mechanical/molecular mechanical (QM/MM) approach are able to describe the chemical reactions and redox processes catalyzed by enzymes. Ab initio QM/MM methods capitalize on the accuracy and reliability of the associated quantum mechanical approaches, however at a much higher computational cost compared with corresponding semiempirical quantum mechanical ap- proaches. Thus reaction path and free energy calculations based on ab initio QM/MM methods encounter unique challenges in simulation times and phase space sampling. This proposal aims to develop further the ab initio QM/MM methodology and its application to the studies of redox processes and mechanisms of chemical reactions in important enzymes. The long-term goal is to develop and establish density functional theory-based QM/MM simulation as an equal partner with experiments for the study of enzymes and to provide detailed insight into chemical reaction and redox reaction mechanisms in biological systems. The ab initio QM/MM-MFEP method has been developed recently to overcome some of the difficul- ties encountered in previous ab initio QM/MM approaches for obtaining minimum energy reaction paths. This proposal aims to develop the QM/MM-MFEP method further into a comprehensive and accurate method for the simulation of redox processes in solution and in enzymes using ab initio QM/MM meth- ods. The QM/MM methodology will be used to investigate several important systems: (1) The redox poten- tials in wild-type and single-site variants of the copper protein enzyme peptidyglycine alpha-hydroxylating monooxygenase (PHM), which is a prototype for the two copper family enzymes that includes dopamine beta-monooxygenase and tyramine beta-monooxygenase. (2) Human DNA polymerase , which catalyzes the phosphoryl-transfer reaction in DNA synthesis. (3) Sulfatases, which controls the state of sulfation of proteins, carbohydrates, lipids and steroids, and may produce the largest rate enhancements that are generated by any enzyme. (4) Peptidoglycan recycling enzyme, which catalyze phosphoryl transfer and hydrolysis. The proposed work will lead to the advancement of theoretical and computational methodology and the understanding of important enzyme reaction mechanisms. In addition, it will also serve to aid in the design of new drugs and enzyme inhibitors.

Public Health Relevance

Understanding chemical reactions and redox processes in solution and in enzymes is of ultimate impor- tance. In biological systems, most biological functions are accomplished through the binding of ligands with proteins and/or a series of chemical reactions catalyzed by specific enzymes with different efficiency and specificity. The structure-function relationship and the catalytic role of enzymes are thus fundamental subjects in biochemical research. They are also essential for the development of new or better inhibitors and enzymes, which have important practical applications, ranging from drug design to the development of novel catalysts for drug synthesis. As an increasing amount of structural information for proteins and enzymes becomes available, the structure-function relationship becomes an even more important link in biological science. Quantitative tools such as simulations will make key contributions to the investigation of this topic. This proposal aims at developing methods for simulating chemical and redox processes catalyzed by enzymes, and investigating the mechanisms of important enzymes-copper protein enzyme peptidyglycine alpha-hydroxylating monooxygenase, human DNA polymerase, sulfatases, and peptidoglycan recycling enzyme. The proposed work will lead to significant advances in research tools for studying enzymes. It will contribute to the understanding of life processes, as well as aiding in the design of inhibitors and drugs.

National Institute of Health (NIH)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Preusch, Peter
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Duke University
Schools of Arts and Sciences
United States
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Shen, Lin; Yang, Weitao (2016) Quantum Mechanics/Molecular Mechanics Method Combined with Hybrid All-Atom and Coarse-Grained Model: Theory and Application on Redox Potential Calculations. J Chem Theory Comput 12:2017-27
Wang, Hao; Yang, Weitao (2016) Determining polarizable force fields with electrostatic potentials from quantum mechanical linear response theory. J Chem Phys 144:224107
Yang, Yang; Shen, Lin; Zhang, Du et al. (2016) Conical Intersections from Particle-Particle Random Phase and Tamm-Dancoff Approximations. J Phys Chem Lett 7:2407-11
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De Vleeschouwer, Freija; Chankisjijev, Artiom; Yang, Weitao et al. (2013) Pushing the boundaries of intrinsically stable radicals: inverse design using the thiadiazinyl radical as a template. J Org Chem 78:3151-8
Wu, Pan; Chaudret, Robin; Hu, Xiangqian et al. (2013) Noncovalent Interaction Analysis in Fluctuating Environments. J Chem Theory Comput 9:2226-2234
Wang, Jun; Yang, Weitao (2013) Concerted proton transfer mechanism of Clostridium thermocellum ribose-5-phosphate isomerase. J Phys Chem B 117:9354-61
Chaudret, Robin; Parks, Jerry M; Yang, Weitao (2013) Pseudobond parameters for QM/MM studies involving nucleosides, nucleotides, and their analogs. J Chem Phys 138:045102
Hu, Xiangqian; Jin, Yingdi; Zeng, Xiancheng et al. (2012) Liquid water simulations with the density fragment interaction approach. Phys Chem Chem Phys 14:7700-9
Wu, Pan; Cisneros, G Andres; Hu, Hao et al. (2012) Catalytic mechanism of 4-oxalocrotonate tautomerase: significances of protein-protein interactions on proton transfer pathways. J Phys Chem B 116:6889-97

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