The goal of this Program Project, entitled Protein Dynamics in Enzymatic Catalysis, is to study atomic motion in enzymes. We propose to study concepts of how the dynamical nature of proteins affects enzymic function and the energy landscape of enzymes from enzyme-substrate to on-enzyme transition state transition state formation. We bring together a skilled research group of diverse backgrounds all aimed at understanding enzyme function. Importantly, we bring to bear unique, advanced, and effective experimental and theoretical approaches sensitive to the evolution of protein structure on multiple time scales, from ps to minutes. There are four projects and two cores. Project 1: 'Energy Landscapes Encoding Function in LDH Investigated Over Broad Time Scales'will (1) probe how conformational motion from picoseconds to milliseconds contributes transition state formation in lactate dehydrogenase and how motions on different timescales are related to each other and (2) probe the contribution of promoting vibrations to enzymic catalysis. Project 2: 'Dynamics and the Transition State of Purine Nucleoside Phosphorylase'studies (1) the motions leading to transition state formation in PNP and (2) the nature of the transition state in PNP by locating and characterizing dynamic promoting vibrations and by generating a vibrationally altered enzyme whose local and collective bond dynamics alter the probability of reaching the transition state. Project 3: 'Mapping the Energy Landscape of Catalysis in DHFR'aims to (1) determine the dynamics of substrate binding and Michaelis complex formation and coupled protein motions in dihydrofolate reductase;(2) determine the dynamics of proton transfer in DHFR;and (3) determine the role of promoting vibrations in the catalytic reaction of DHFR. Project 4: 'Energy Landscapes and Motional Timescales in Enzyme Catalysis'investigates dynamics in enzymes on multiple time scales and provides theoretical support to the other projects by (1) investigating how longer time conformational motion contributes to enzyme function, and in atomic detail, how motions at different timescales are related to each other;(2) determining how protein architecture results in vibrational energy """"""""channeling"""""""" in enzymes and study how mutation effects this architecture;and (3) elucidating the concept of the tight binding of the transition state and show how, in a specific reaction, the transition state is approached and transited. The Equipment Core (Core A) supports the specialized comprehensive suite of instrumentation for the Program. The Administrative Core (Core B) administers the Program Project.

Public Health Relevance

Enzymes are targets for a broad array of Pharmaceuticals. How atomic motion in proteins brings about enzymatic catalysis is very poorly understood. The detailed structure of the enzymatic transition state is a powerful target for drug design, and increased knowledge of how enzymes form this state is fundamental for all catalysts and specifically for designing new classes of drugs.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Program Projects (P01)
Project #
5P01GM068036-10
Application #
8463554
Study Section
Special Emphasis Panel (ZRG1-BCMB-N (40))
Program Officer
Wehrle, Janna P
Project Start
2004-05-01
Project End
2014-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
10
Fiscal Year
2013
Total Cost
$1,785,056
Indirect Cost
$531,248
Name
Albert Einstein College of Medicine
Department
Biochemistry
Type
Schools of Medicine
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
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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