Based on structural information from X-ray and NMR experiments, computational simulations performed using molecular dynamics and the quantum mechanical/molecular mechanical (QM/MM) approach are able to describe the mechanisms of chemical reactions 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 approaches. Thus reaction path and activation free energy calculations based on ab initio QM/MM methods encounter unique challenges in simulation timescales and phase space sampling. This proposal aims to develop further the ab initio QM/MM methodology and its application to the investigation of the 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 the structure and chemical reactions of enzymes and to provide detailed insight into chemical reaction mechanisms in biological systems. The ab initio QM/MM-MFEP method has been developed recently to overcome some of the difficulties encountered in previous ab initio QM/MM approaches for obtaining minimum energy reaction paths. Previous total energy-based methods suffer from a dependence on the local conformations of the protein/solvent environment. In the QM/MM-MFEP method, the reaction system is described via the potential of mean force (PMF) surface of the QM subsystem in the active site, while the large number of MM degrees of freedom describing the rest of the protein and solvent are statistically averaged. This proposal aims to develop the QM/MM-MFEP method further into a comprehensive and accurate method for the simulation of reaction processes in solution and in enzymes using ab initio QM/MM methods. The QM/MM methodology will be used to investigate the reaction mechanism of several important enzymes: (1) Tryptophanyl-tRNA synthetase, which catalyzes the amino acid activation process;(2) Sortase, which recognizes and cleaves peptides, and then covalently links the peptides to cell walls, in association with Gram-positive pathogenic bacteria;and (3) Gram-positive bacterial pili, which play important roles in the biological functions of many bacteria. The proposed work will lead to the advancement of theoretical 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

This proposal aims at developing methods for simulating chemical processes catalyzed by enzymes, and investigating the catalytic mechanisms of certain important enzymes. The proposed work will lead to significant advances in research tools for studying enzymes. Because enzymes catalyze most of the chemical processes in living organisms, 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)
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 C
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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
Fusco, Diana; Headd, Jeffrey J; De Simone, Alfonso et al. (2014) Characterizing protein crystal contacts and their role in crystallization: rubredoxin as a case study. Soft Matter 10:290-302
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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