Previous work in this program project has identified motions that are involved in the catalytic function of enzymes. The hypothesis for our work in this renewal application is that by using theoretical and computational methods we can identify the structural elements that create dynamics related to catalysis on all timescales, and through these means we may create protein dynamics design paradigms for both rate enhancement, and enzyme inhibition. In order to complete this research program we will work on 5 distinct areas that are: 1) we will identify conformational movements necessary on all timescales for reaction. Just as we have followed trajectories and identified protein dynamics that form promoting vibrations and are part of the reaction coordinate, we will extend these calculations to the timescale of enzyme turnover. 2) We will identify structural elements in specific enzyme systems (lactate dehydrogenase and purine nucleoside phosphorylase) that create the specific dynamics. 3) We will identify allosteric binding sites and determine the effect of binding on protein dynamics. 4) We will identify how dynamics is involved in transition state inhibitor binding. 5) we will propose a redesign of "heavy" PNP that corrects dynamic defects we have previously identified and restores normal catalytic function. The overall thrust to all of the work in this program project has been the identification of dynamics as a central feature in enzyme function from the selection of a catalytically competent conformational substate to rapid promoting vibrations. We now proceed to the next step in this program - identification of dynamics as a design element in enzyme function. We propose to begin the process of developing this concept as a protein engineering tool.
Enzymes perform the chemistry of life. They do so with far greater efficiency and specificity than any non-biological catalyst. One of the great challenges of our day is finding the design principles of enzymes so that we may create synthetic biological catalysts. The work described in this project will advance this goal.
|Pan, Xiaoliang; Schwartz, Steven D (2016) Conformational Heterogeneity in the Michaelis Complex of Lactate Dehydrogenase: An Analysis of Vibrational Spectroscopy Using Markov and Hidden Markov Models. J Phys Chem B 120:6612-20|
|Dzierlenga, Michael W; Schwartz, Steven D (2016) Targeting a Rate-Promoting Vibration with an Allosteric Mediator in Lactate Dehydrogenase. J Phys Chem Lett 7:2591-6|
|Antoniou, Dimitri; Schwartz, Steven D (2016) Phase Space Bottlenecks in Enzymatic Reactions. J Phys Chem B 120:433-9|
|Wang, Zhen; Antoniou, Dimitri; Schwartz, Steven D et al. (2016) Hydride Transfer in DHFR by Transition Path Sampling, Kinetic Isotope Effects, and Heavy Enzyme Studies. Biochemistry 55:157-66|
|Dzierlenga, M W; Varga, M J; Schwartz, S D (2016) Path Sampling Methods for Enzymatic Quantum Particle Transfer Reactions. Methods Enzymol 578:21-43|
|Zoi, Ioanna; Suarez, Javier; Antoniou, Dimitri et al. (2016) Modulating Enzyme Catalysis through Mutations Designed to Alter Rapid Protein Dynamics. J Am Chem Soc 138:3403-9|
|Reddish, Michael J; Vaughn, Morgan B; Fu, Rong et al. (2016) Ligand-Dependent Conformational Dynamics of Dihydrofolate Reductase. Biochemistry 55:1485-93|
|Varga, Matthew J; Schwartz, Steven D (2016) Enzymatic Kinetic Isotope Effects from First-Principles Path Sampling Calculations. J Chem Theory Comput 12:2047-54|
|Pan, Xiaoliang; Schwartz, Steven D (2015) Free energy surface of the Michaelis complex of lactate dehydrogenase: a network analysis of microsecond simulations. J Phys Chem B 119:5430-6|
|Dzierlenga, Michael W; Antoniou, Dimitri; Schwartz, Steven D (2015) Another Look at the Mechanisms of Hydride Transfer Enzymes with Quantum and Classical Transition Path Sampling. J Phys Chem Lett 6:1177-81|
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