# NOT-OD-20-073 Administrative Supplement for: "Investigation of DNA Modifying Enzymes by Computational Simulations: Development and Applications"

> **NIH NIH R01** · UNIVERSITY OF NORTH TEXAS · 2020 · $100,000

## Abstract

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 κ), 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.

## Key facts

- **NIH application ID:** 10156175
- **Project number:** 3R01GM108583-08S1
- **Recipient organization:** UNIVERSITY OF NORTH TEXAS
- **Principal Investigator:** Gerardo Andres Cisneros
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $100,000
- **Award type:** 3
- **Project period:** 2014-05-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10156175

## Citation

> US National Institutes of Health, RePORTER application 10156175, NOT-OD-20-073 Administrative Supplement for: "Investigation of DNA Modifying Enzymes by Computational Simulations: Development and Applications" (3R01GM108583-08S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10156175. Licensed CC0.

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