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)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-BCMB-N (40))
Program Officer
Wehrle, Janna P
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Albert Einstein College of Medicine
Schools of Medicine
United States
Zip Code
Einarsdóttir, Olöf; McDonald, William; Funatogawa, Chie et al. (2015) The pathway of O?to the active site in heme-copper oxidases. Biochim Biophys Acta 1847:109-18
Reddish, Michael J; Peng, Huo-Lei; Deng, Hua et al. (2014) Direct evidence of catalytic heterogeneity in lactate dehydrogenase by temperature jump infrared spectroscopy. J Phys Chem B 118:10854-62
Kise, Drew P; Magana, Donny; Reddish, Michael J et al. (2014) Submillisecond mixing in a continuous-flow, microfluidic mixer utilizing mid-infrared hyperspectral imaging detection. Lab Chip 14:584-91
Wang, Zhen; Singh, Priyanka; Czekster, Clarissa M et al. (2014) Protein mass-modulated effects in the catalytic mechanism of dihydrofolate reductase: beyond promoting vibrations. J Am Chem Soc 136:8333-41
Peng, Huo-Lei; Deng, Hua; Dyer, R Brian et al. (2014) Energy landscape of the Michaelis complex of lactate dehydrogenase: relationship to catalytic mechanism. Biochemistry 53:1849-57
Masterson, Jean E; Schwartz, Steven D (2014) The enzymatic reaction catalyzed by lactate dehydrogenase exhibits one dominant reaction path. Chem Phys 442:132-136
Li, Guifeng; Magana, Donny; Dyer, R Brian (2014) Anisotropic energy flow and allosteric ligand binding in albumin. Nat Commun 5:3100
Schramm, Vern L (2013) Transition States, analogues, and drug development. ACS Chem Biol 8:71-81
Masterson, Jean E; Schwartz, Steven D (2013) Changes in protein architecture and subpicosecond protein dynamics impact the reaction catalyzed by lactate dehydrogenase. J Phys Chem A 117:7107-13
Motley, Matthew W; Schramm, Vern L; Schwartz, Steven D (2013) Conformational freedom in tight binding enzymatic transition-state analogues. J Phys Chem B 117:9591-7

Showing the most recent 10 out of 62 publications