Quantum effects on nuclear motion may play an important role in certain enzymatically- catalyzed reactions. While methods to include quantum mechanics in electron distributions for biological systems are now mature (for example QM/MM methods) methods to include quantum effects on the dynamics of nuclei are far less well developed. In addition, there is a need to discover atomic details regarding the mechanism of biochemical reactions with no need for preconceived reaction mechanism. The program described in this application is designed to develop and apply methods that answer these needs. We will implement a new method that combines centroid quantum dynamics with transition path sampling to include quantum effects in biological chemistry. If time allows we will apply the method to quantify the importance of nuclear quantum effects in the reaction catalyzed by yeast alcohol dehydrogenase. In order to do this we will study the following 3 specific aims:
Specific Aim 1 : We will develop and apply a method to include quantum dynamics within the framework of Transition Path Sampling (TPS.) Specific Aim 2 We will develop and apply methods to calculate the reaction mechanism as affected by quantum dynamics, and also to calculate the rates of the chemical step of enzymatically catalyzed reactions including and excluding quantum dynamic effects.
Specific Aim 3 : We will apply the methods developed in Specific Aims 1 and 2 to the study of the reaction catalyzed by yeast alcohol dehydrogenase (YADH.)

Public Health Relevance

Quantum effects in the atomic motions of enzymatically-catalyzed reactions are difficult to study, and there is currently lack of agreement between experiment and theory. Theoretical methods that include explicit quantum dynamics that can quantify such phenomena as the importance of tunneling in atomic transfer are developed in this application and applied to the reaction catalyzed by yeast alcohol dehydrogenase.

National Institute of Health (NIH)
Exploratory/Developmental Grants (R21)
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Macromolecular Structure and Function E Study Section (MSFE)
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Lyster, Peter
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Albert Einstein College of Medicine
Schools of Medicine
United States
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Varga, Matthew J; Schwartz, Steven D (2016) Enzymatic Kinetic Isotope Effects from First-Principles Path Sampling Calculations. J Chem Theory Comput 12:2047-54
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
Antoniou, Dimitri; Ge, Xiaoxia; Schramm, Vern L et al. (2012) Mass Modulation of Protein Dynamics Associated with Barrier Crossing in Purine Nucleoside Phosphorylase. J Phys Chem Lett 3:3538-3544