# Polarizable Force Field for Proteins and Lipids

> **NIH NIH R01** · UNIVERSITY OF CHICAGO · 2022 · $397,712

## Abstract

PROJECT SUMMARY
Molecular dynamics (MD) simulations based on atomistic models play an increasingly important role in
understanding the fundamental physical forces driving the structure and dynamics of biological membranes.
However, to have meaningful simulations, accurate and empirical force fields (FFs) are necessary. Although
nonpolarizable additive FFs are useful approximations, polarizable models of biological membranes are
needed to account for their complex molecular nature. The present efforts to develop and optimize a
polarizable FF for lipids will allow fundamental simulation studies of a broad range of processes associated
with biological membranes. During the last funding period we made significant progress with the development
of a polarizable FF based on the classical Drude oscillator model. The Drude FF has been implemented in
CHARMM, NAMD, ChemShell QM/MM, GROMACS and the OpenMM GPU suite, allowing for unbiased
simulations on the microsecond time scale as well as simulations exploiting a range of enhanced sampling
technologies. We can already model water, ions, proteins, nucleic acids, carbohydrates, and a few neutral
phospholipids. At this point there is a critical need to expand the type of phospholipids covered by the Drude
FF to enable the modeling of a wider range of biological membrane systems, as over one third of all MD
simulations of biological systems involve bilayer membranes. Polarizable models of biological membranes are
necessary to account for their complex molecular nature, where a variety of strong electrostatic factors
compete with one another over microscopic length-scales. The plan is to perform a global optimization and
validation of the Drude FF for lipids using structural, dynamical, and mechanical information as physical target
membrane data for the optimization, and improve the treatment of nonbonded interactions via a lattice sum of
the long-range van der Waals dispersion (LJ-PME), and simultaneously extend the Drude FF to cover charged
lipids with a special attention to the strong interactions of ions with the polar headgroup (Aim 1). We will then
use the refined Drude FF to study fundamental aspects biomembrane electrostatics and elucidate the
contribution of electronic polarization on the fundamental electrostatics features of biological membranes (Aim
2) with a study of the classical concept of ζ-potential and the properties of membrane-bound voltage-sensitive
dyes with polarizable models for the ground and excited state. Lastly, we will develop accurate polarizable
models of phosphatidylinositol-4,5-bisphosphate (PIP2), with a special attention to the interactions with
monovalent and divalent cations to study ion-induced domain formation and lateral clustering of PIP2 (Aim 3).

## Key facts

- **NIH application ID:** 10477289
- **Project number:** 5R01GM072558-15
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** BENOIT ROUX
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $397,712
- **Award type:** 5
- **Project period:** 2005-02-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10477289

## Citation

> US National Institutes of Health, RePORTER application 10477289, Polarizable Force Field for Proteins and Lipids (5R01GM072558-15). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10477289. Licensed CC0.

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