# Exploring Electronic Polarization in Biomolecular Folding and Interactions

> **NIH NIH R35** · VIRGINIA POLYTECHNIC INST AND ST UNIV · 2024 · $360,647

## Abstract

PROJECT SUMMARY
Targeting transient or highly dynamic states of biomolecules with small molecule drugs is a major challenge that
must be overcome to advance therapeutic design for human diseases including Alzheimer’s, Parkinson’s,
cancer, and viral infections. Studying biomolecules that rapidly change shape or that adopt targetable structures
infrequently is a task that is well suited to theoretical investigations in the context of computer-aided drug design.
Simulation methods can relate structure to energy, and can provide quantitative descriptions of how small
molecules modulate biomolecular structure and dynamics. Our laboratory applies polarizable molecular
dynamics (MD) simulations to amyloidogenic proteins and G-quadruplexes (GQs), for which the effects of
induced electronic polarization are critical for describing their dynamics. In this application, we propose a
research program that seeks to advance drug design efforts against (1) monomeric and membrane-embedded,
oligomeric amyloidogenic proteins and (2) G-quadruplexes involved in cancer and viral infections. Throughout
these investigations, we focus on the role of induced electronic polarization and electric fields in driving
conformational change and ligand binding. We base these efforts on our previous discoveries in how induced
polarization influences critical behaviors in these systems and how electric fields exerted within the biomolecules
may drive fundamental behaviors. During the project period, we propose to employ cutting-edge strategies for
investigating the conformational ensembles of several amyloidogenic peptides in aqueous and phospholipid
membranes. We will use structural insights from these simulations to propose new targets for small-molecule
design. Similarly, we will investigate structurally diverse GQs in the presence and absence of known ligands to
understand the factors driving ligand binding. We will expand upon these efforts with simulations and virtual
screening efforts that aim to design new small molecules that will bind GQs with greater specificity than is
possible with generic aromatic features. In both of these projects, we will conduct experimental validation of
proposed high-affinity compounds using a variety of spectroscopic and biophysical methods. The specific goals
for the five-year project period are to (1) determine the conformational free energy landscapes of amyloidogenic
proteins and identify dynamic targets and (2) identify substates of GQ ensembles that can be used for high-
affinity small-molecule design. These projects reflect the overall vision of the research program, which is to apply
the most accurate models and rigorous methods to investigate biomolecular dynamics at the atomic level to
understand the molecular basis of disease and to intervene with small-molecule therapeutics.

## Key facts

- **NIH application ID:** 10840206
- **Project number:** 2R35GM133754-06
- **Recipient organization:** VIRGINIA POLYTECHNIC INST AND ST UNIV
- **Principal Investigator:** Justin Alan Lemkul
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $360,647
- **Award type:** 2
- **Project period:** 2019-08-01 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10840206

## Citation

> US National Institutes of Health, RePORTER application 10840206, Exploring Electronic Polarization in Biomolecular Folding and Interactions (2R35GM133754-06). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10840206. Licensed CC0.

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