# Exploring Electronic Polarization in Biomolecular Folding and Interactions

> **NIH NIH R35** · VIRGINIA POLYTECHNIC INST AND ST UNIV · 2022 · $229,304

## Abstract

PROJECT SUMMARY
The forces driving conformational change of proteins and nucleic acids in aqueous solution and proteins in lipid
membranes remain incompletely characterized. Theoretical methods are well suited to establishing relationships
between structure and energetics, providing critical information for determining the forces underlying biological
processes in different cellular microenvironments. Our laboratory uses molecular dynamics (MD) simulations
with the recently developed Drude polarizable force field to investigate the conformational ensembles of model
peptides and proteins, nucleic acids, and lipid membranes. In this application, we propose a research program
that breaks new ground in exploring (1) the forces driving the unfolding of amyloidogenic peptides with and
without post-translational modifications, (2) the effects of ions and noncanonical interactions in stabilizing DNA
G-quadruplexes (GQ), and (3) the role of induced electronic polarization on small-molecule partitioning and
peptide folding in phospholipid membranes. The unifying theme of these projects is an examination of the
atomistic details driving conformational change with specific emphasis on the role of induced electronic
polarization. During the project period, we propose to investigate conformational ensembles of several
amyloidogenic peptides to understand the role of induced electronic polarization on peptide-peptide and peptide-
water interactions (hydrogen bonding, electrostatic clashes, and other induced dipole-dipole interactions).
Similarly, we will investigate DNA GQ with different folds (parallel, antiparallel, and mixed) to characterize how
their nucleobase properties (alignment, dipole moments, etc.) and loop conformational ensembles are impacted
by different monovalent ions and noncanonical base-base and base-phosphate interactions that stabilize GQ.
The final project comprises simulations of peptides and small molecules in lipid membranes to understand
partitioning, thermodynamics, and the strength of hydrogen bonds and other intrapeptide and intermolecular
interactions in the hydrophobic core of the membrane, as these interactions are tied to the polarity of the
surrounding medium. The specific goals for the five-year project period are to (1) determine interactions among
amino acids in amyloidogenic peptides that dictate conformational change, (2) characterize the relative
contributions of ions, water, and noncanonical base interactions in stabilizing DNA GQ, and (3) quantify the free
energy changes associated with peptide folding and small-molecule partitioning in membranes. These projects
are representative of the overall vision of the research program, to apply rigorous theoretical methods to complex
biomolecules to understand the molecular basis for a variety of diseases (including neurodegenerative disorders
and several types of cancer) and to use the resulting information to carry out computer-aided drug design against
new biomolecular target...

## Key facts

- **NIH application ID:** 10437620
- **Project number:** 5R35GM133754-04
- **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:** 2022
- **Award amount:** $229,304
- **Award type:** 5
- **Project period:** 2019-08-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10437620

## Citation

> US National Institutes of Health, RePORTER application 10437620, Exploring Electronic Polarization in Biomolecular Folding and Interactions (5R35GM133754-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10437620. Licensed CC0.

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