# Investigation of DNA Modifying Enzymes by Computational Simulations: Development and Applications

> **NIH NIH R01** · UNIVERSITY OF TEXAS DALLAS · 2021 · $311,998

## Abstract

Investigation of DNA Modifying Enzymes by Computational Simulations: Development and Applications
Project Summary
The accurate synthesis, maintenance, repair, and modification of DNA is crucial for organismal survival since
errors in DNA can lead to the onset of different diseases. Therefore, enzymes related to DNA transactions
need to perform their activities accurately and efficiently. Mutations arising from exogenous or endogenous
factors can result in changes that affect the structure and/or function of these enzymes. There are a large
number of enzyme families involved in the synthesis, repair and modification of DNA. Two of these families
involve DNA polymerases (DNA pols) and AID/APOBEC enzymes. The former family includes over 16 human
DNA pols, which are responsible for the accurate synthesis and repair of DNA. The AID/APOBEC enzymes
comprise several members, including A3G and A3H, are involved in targeted deamination of DNA bases, and
are key players in immune response. Understanding the detailed structure, function and mechanism of native
and mutant versions of these enzymes can help in myriad ways, from insights on basic biochemical issues
such as inter-molecular interactions to information that can aid in the development of diagnostic and/or
therapeutic treatments. 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 present 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 enzyme...

## Key facts

- **NIH application ID:** 10539220
- **Project number:** 7R01GM108583-10
- **Recipient organization:** UNIVERSITY OF TEXAS DALLAS
- **Principal Investigator:** Gerardo Andres Cisneros
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $311,998
- **Award type:** 7
- **Project period:** 2014-05-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10539220

## Citation

> US National Institutes of Health, RePORTER application 10539220, Investigation of DNA Modifying Enzymes by Computational Simulations: Development and Applications (7R01GM108583-10). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10539220. Licensed CC0.

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