# Simulation of Proton and Hydride Transfer in Enzymes

> **NIH NIH R37** · YALE UNIVERSITY · 2020 · $361,083

## Abstract

The broad, long-term objectives of this research are to elucidate the fundamental principles and mechanisms
of hydrogen transfer in both protein and RNA enzyme catalysis. These objectives will be accomplished with
a wide range of theoretical and computational methods, including classical molecular dynamics simulations
and mixed quantum mechanical/molecular mechanical simulations that provide atomic-level information
about Structural rearrangements and conformational motions. These calculations will probe the roles of
hydrogen bonding, active site reorganization, hydrogen tunneling, active site water molecules, electrostatics,
and conformational motions in both protein and RNA enzyme catalysis. These theoretical studies will be
performed in close collaboration with experimental groups, assisting in the interpretation of experimental
data and providing experimentally testable predictions. The protein enzyme projects will focus on soybean
lipoxygenase and human DNA polymerase eta, and the RNA enzyme projects will focus on the gImS and
twister ribozymes. Soybean lipoxygenase serves as a prototype for investigating hydrogen tunneling in
enzymes because it exhibits unusually large hydrogen/deuterium kinetic isotope effects. Theoretical
investigations of the temperature and pressure dependence of the rates and kinetic isotope effects of wild-
type and mutant enzymes will provide insight into the motions that impact hydrogen tunneling. Human DNA
polymerase eta enables the replication of DNA that has been damaged by exposure to ultraviolet rays, and
understanding its mechanism has significant implications for skin cancer prevention and treatment.
Simulations of this enzyme will provide insight into the mechanism of this biomedically important enzyme.
The gImS and twister ribozymes catalyze self-cleavage reactions that are essential for modulating protein
synthesis and various RNA processing reactions. Theoretical studies of these ribozymes will illuminate their
mechanisms and may assist in the development of ribozymes for use as therapeutic agents to cleave
pathogenic RNAs. All of these studies are relevant to public health because the resulting fundamental
insights could facilitate the design of more effective drugs for a wide range of diseases.
RELEVANCE (See instructions):
These studies are relevant to public health because the elucidation of fundamental principles of enzyme
catalysis will facilitate the design of more efficient enzymes, thereby potentially assisting in the development
of more effective drugs for a broad range of diseases, including skin cancer. Insights into RNA catalysis may
assist in the development of RNA enzymes for use as therapeutic agents to cleave pathogenic RNAs.

## Key facts

- **NIH application ID:** 9926260
- **Project number:** 5R37GM056207-26
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** SHARON HAMMES-SCHIFFER
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $361,083
- **Award type:** 5
- **Project period:** 1998-05-01 → 2021-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9926260

## Citation

> US National Institutes of Health, RePORTER application 9926260, Simulation of Proton and Hydride Transfer in Enzymes (5R37GM056207-26). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9926260. Licensed CC0.

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