# Exploring the Dynamics of Prolyl-tRNA Synthetases: Towards Developing a Screening Method for Species-Specific Inhibitors

> **NIH NIH R15** · UNIVERSITY OF WISCONSIN EAU CLAIRE · 2021 · $397,331

## Abstract

The proposed work is the renewal of our previously funded NIH grant proposal. Our research is focused on the
interplay between enzyme dynamics and catalysis. For the past twelve years, we have developed techniques
and protocols to explore some pressing issues of enzymology − the precise role of dynamics in catalysis, the
evolution of functional dynamics across species, and the impact of molecular crowding on catalysis. We are
using prolyl-tRNA synthetase (ProRS) as our model enzyme, which belongs to the superfamily of enzymes called
aminoacyl-tRNA synthetases (AARSs). Because of their central role in protein synthesis, AARSs have emerged
as attractive targets for anti-infective drug development. Common to all kingdoms of life, the active site of ProRSs
from different species bear significant sequence similarity. As a result, drug molecules targeting a pathogenic
enzyme's catalytic site could bind to the human counterpart, thus resulting in cell toxicity. Therefore, we are
attempting to utilize proteins' intrinsic dynamics for designing and screening species-specific inhibitors for
pathogenic ProRSs.
 Currently, the work is at a juncture, where a thorough investigation using state-of-the-art computational
techniques, standardized biochemical protocols, and well-established spectroscopic methods could provide
deeper insights into the above-mentioned topics. Herein, we propose a comprehensive study, which blends
classical and modern biochemical and biophysical techniques to address these core questions of enzymology.
The proposed study will investigate in detail the interplay of electrostatics and dynamics in a quest for the
evolutionary origin of the enzyme's catalytic power. Additionally, the proposed study will strive to determine the
effects of the crowded cellular milieu on our model enzyme. This will be accomplished by following the molecular
details of enzymes' conformational dynamics, substrate recognition, and catalysis in crowded and confined
environments. Completion of the proposed work could lead to new possibilities for protein design and drug
discovery. In addition to the scientific relevance, the proposed work would provide an outstanding opportunity
for our students; participation will yield the development of hands-on laboratory skills while deepening their
understanding of these fundamental biophysical concepts. Furthermore, the experience and skills acquired
through participation will lead to preparedness for the workforce, as well as opportunities to thrive in graduate
and professional schools.

## Key facts

- **NIH application ID:** 10203549
- **Project number:** 2R15GM117510-02
- **Recipient organization:** UNIVERSITY OF WISCONSIN EAU CLAIRE
- **Principal Investigator:** Sudeep Bhattacharyay
- **Activity code:** R15 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $397,331
- **Award type:** 2
- **Project period:** 2016-02-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10203549

## Citation

> US National Institutes of Health, RePORTER application 10203549, Exploring the Dynamics of Prolyl-tRNA Synthetases: Towards Developing a Screening Method for Species-Specific Inhibitors (2R15GM117510-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10203549. Licensed CC0.

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