We propose to bring our Enzyme Dynamics Program into an uncharted area of inquiry with this renewal: bridging the gap from observation to design. Progress made thus far, developing powerful new approaches and a deep knowledge of the dynamical nature of enzymes, has set the stage for a fundamentally new approach to enzyme and inhibitor design based on dynamics. The overall objective of the research is the development of rational design principles based on dynamics for both 'allosteric'effectors and inhibitors for naturally occurring enzymes and rationally designed synthetic enzymes. The key to achieving this goal is to understand protein architectural design features that yield specific, functionally important dynamics. We bring together a skilled research group of diverse backgrounds all aimed at understanding enzyme function. This group has proven its ability to work closely in collaborative research over a decade. Importantly, we bring to bear unique, advanced, and effective experimental and theoretical approaches sensitive to the characteristics of protein structure and the dynamics this structure engenders on multiple time scales, from fs to ms or longer. This Program consists of four Projects with, collectively, two overall Aims: (1) To determine, via integrated application of experiment and theory, the elements of protein structure that create specific dynamics that are part of enzymatic catalysis on all relevant timescales. We will study how protein dynamics, particularly focused on the energy landscape of the Michaelis complex and motion of the promoting vibrations, is coupled to allostery and how this concept can be expanded to fully elucidate allosteric regulation of proteins. This presents a potential paradigm shift for protein and enzyme regulation via new drug action. In addition, a deeper understanding of transition state passage leaves us with the view that transition state inhibitors often do not function by """"""""locking in"""""""" a specific structure, but rather by preserving dynamics at the transition state. We will investigate this new principle of strong inhibitor bindin via dynamic preservation as a paradigm for enzyme function and inhibition. (2) To use the understanding of how important functional dynamics are coded into the protein structure gained in (1) as a means to manipulate them in order to modify protein function. This objective comprises several parts. One is to design active site inhibitors against the dynamical nature of the enzyme. Another is to design small molecules to modify the dynamical nature through an 'allosteric'action which will either down or up-regulate activity and/or binding of substrate. The third is to develop methods to design rate controlling dynamics on a variety of timescales into engineered enzymes.
Our studies are aimed at determining the elements of protein structure that create specific dynamics important for catalytic mechanism. We will understand design features that either up or down regulate enzymatic activity. This Program Project is perhaps the most advanced in the world to develop our understanding of dynamics in enzyme interactions. The goal of this research is to lay a foundation for the development and rational design of 'allosteric'effectors or active site inhibitors based on dynamics.
|Zoi, Ioanna; Antoniou, Dimitri; Schwartz, Steven D (2017) Incorporating Fast Protein Dynamics into Enzyme Design: A Proposed Mutant Aromatic Amine Dehydrogenase. J Phys Chem B 121:7290-7298|
|Deng, Hua; Vedad, Jayson; Desamero, Ruel Z B et al. (2017) Difference FTIR Studies of Substrate Distribution in Triosephosphate Isomerase. J Phys Chem B 121:10036-10045|
|Khrapunov, Sergei; Chang, Eric; Callender, Robert H (2017) Thermodynamic and Structural Adaptation Differences between the Mesophilic and Psychrophilic Lactate Dehydrogenases. Biochemistry 56:3587-3595|
|Eismin, Ryan J; Munusamy, Elango; Kegel, Laurel L et al. (2017) Evolution of Aggregate Structure in Solutions of Anionic Monorhamnolipids: Experimental and Computational Results. Langmuir 33:7412-7424|
|Peng, Huo-Lei; Callender, Robert (2017) Mechanistic Analysis of Fluorescence Quenching of Reduced Nicotinamide Adenine Dinucleotide by Oxamate in Lactate Dehydrogenase Ternary Complexes. Photochem Photobiol 93:1193-1203|
|Davis, Caitlin M; Reddish, Michael J; Dyer, R Brian (2017) Dual time-resolved temperature-jump fluorescence and infrared spectroscopy for the study of fast protein dynamics. Spectrochim Acta A Mol Biomol Spectrosc 178:185-191|
|Reddish, Michael J; Callender, Robert; Dyer, R Brian (2017) Resolution of Submillisecond Kinetics of Multiple Reaction Pathways for Lactate Dehydrogenase. Biophys J 112:1852-1862|
|Zoi, Ioanna; Antoniou, Dimitri; Schwartz, Steven D (2017) Electric Fields and Fast Protein Dynamics in Enzymes. J Phys Chem Lett 8:6165-6170|
|Munusamy, Elango; Luft, Charles M; Pemberton, Jeanne E et al. (2017) Structural Properties of Nonionic Monorhamnolipid Aggregates in Water Studied by Classical Molecular Dynamics Simulations. J Phys Chem B 121:5781-5793|
|Brás, Natércia F; Fernandes, Pedro A; Ramos, Maria J et al. (2017) Mechanistic Insights on Human Phosphoglucomutase Revealed by Transition Path Sampling and Molecular Dynamics Calculations. Chemistry :|
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