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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Program Projects (P01)
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Special Emphasis Panel (ZRG1-BCMB-N (40))
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Wehrle, Janna P
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Albert Einstein College of Medicine
Schools of Medicine
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Harijan, Rajesh K; Zoi, Ioanna; Antoniou, Dimitri et al. (2018) Inverse enzyme isotope effects in human purine nucleoside phosphorylase with heavy asparagine labels. Proc Natl Acad Sci U S A 115:E6209-E6216
Luft, Charles M; Munusamy, Elango; Pemberton, Jeanne E et al. (2018) Molecular Dynamics Simulation of the Oil Sequestration Properties of a Nonionic Rhamnolipid. J Phys Chem B 122:3944-3952
Chen, Xi; Schwartz, Steven D (2018) Directed Evolution as a Probe of Rate Promoting Vibrations Introduced via Mutational Change. Biochemistry 57:3289-3298
Kozlowski, Rachel; Ragupathi, Ashwin; Dyer, R Brian (2018) Characterizing the Surface Coverage of Protein-Gold Nanoparticle Bioconjugates. Bioconjug Chem 29:2691-2700
Brás, Natércia F; Fernandes, Pedro A; Ramos, Maria J et al. (2018) Mechanistic Insights on Human Phosphoglucomutase Revealed by Transition Path Sampling and Molecular Dynamics Calculations. Chemistry 24:1978-1987
Andrews, Brooke A; Dyer, R Brian (2018) Small molecule cores demonstrate non-competitive inhibition of lactate dehydrogenase. Medchemcomm 9:1369-1376
Schramm, Vern L; Schwartz, Steven D (2018) Promoting Vibrations and the Function of Enzymes. Emerging Theoretical and Experimental Convergence. Biochemistry 57:3299-3308
Vaughn, Morgan B; Zhang, Jianyu; Spiro, Thomas G et al. (2018) Activity-Related Microsecond Dynamics Revealed by Temperature-Jump Förster Resonance Energy Transfer Measurements on Thermophilic Alcohol Dehydrogenase. J Am Chem Soc 140:900-903
Khrapunov, Sergei (2018) The Enthalpy-entropy Compensation Phenomenon. Limitations for the Use of Some Basic Thermodynamic Equations. Curr Protein Pept Sci 19:1088-1091
Peng, Huo-Lei; Callender, Robert (2018) Mechanism for Fluorescence Quenching of Tryptophan by Oxamate and Pyruvate: Conjugation and Solvation-Induced Photoinduced Electron Transfer. J Phys Chem B 122:6483-6490

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