Supplement for: Investigation of DNA Modifying Enzymes by Computational Simulations: Development and Applications Project Summary Computational simulations based on classical molecular dynamics (MD) and hybrid quantum mechanical (QM)/molecular mechanical (MM) methods have been shown to provide a very important tool to investigate the reaction mechanism of enzymes with atomic level detail. Our long-term goal is to develop accurate QM/MM methods to understand the mechanism, structure and function of enzymes involved in DNA modification by means of computational simulations. To this end, the goals of the parent proposal are: i) To use MD and QM/MM simulations to study the structure/function/reactivity of wild type and selected mutants, including cancer variants, of two DNA Pols (DNA Pol III, and DNA Pol ?), and one APOBEC enzyme (A3H). ii) To continue the development of LICHEM, our QM/MM software, which interfaces QM programs with advanced anisotropic/polarizable force fields (GEM and AMOEBA) to accurately describe the MM environment; and to extend the QM/MM--minimum free energy path (QM/MM--MFEP) method for anisotropic/polarizable potentials to enable efficient free energy calculations for QM/MM simulations. The detailed understanding of the structure, function and reaction mechanism of the selected DNA pols and APOBEC3H will provide insights into effects of cancer mutants, as well as possible routes to develop inhibitors for these enzymes. Our collaborators, Profs. Penny Beuning, David Rueda and Rahul Kohli, will perform experimental studies based on our computational results. The successful completion of the proposed project will provide an accurate computational tool for the calculation of enzyme reactions, and the generation of structural and mechanistic insights on two important families of enzymes, that may be used to enhance the efficacy of cancer treatments. The purpose of the present supplement request are to expand the scope of the software development to implement MDI (MolSSI Driver Interface) in LICHEM in collaboration with the Molecular Sciences Software Institute (MolSSI). extend and deploy LICHEM to a cloud environment via Azure in collaboration with Microsoft, and implement our own density?based GEM force field in TINKER?HP.
(Relevance) A useful approach to investigate enzymatic reactions related to human health is the combined quantum mechanical/molecular mechanical (QM/MM) approach. We develop and maintain software for classical and QM/MM simulations as well as develop accurate methods for biomolecular calculations. This supplement request focuses on the enhancement of LICHEM by introducing the MolSSI Driver Interface (MDI) and extending LICHEM to a cloud environment and implementation of GEM in TINKER-HP.
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