# Unraveling how Lipophilic Modulators Alter pLGIC Function via Interactions with the M4 Transmembrane Helix

> **NIH NIH K08** · WASHINGTON UNIVERSITY · 2024 · $185,953

## Abstract

Project Summary/Abstract
Dr. Mark Arcario is a cardiothoracic anesthesiologist whose long-term goal is to be an independent physician-
scientist studying molecular mechanisms of allostery in ion channels. His research background is in
computational biophysics of membrane proteins with a focus on the effects of lipids and lipophiles on membrane
protein structure and function. He has a special interest in pentameric ligand-gated ion channels (pLGICs) and
mechanisms of anesthetic action. Several endogenous lipids, including neurosteroids, phospholipids, and fatty
acids, are strong allosteric modulators of pLGICs and it has been suggested that drugs, including anesthetics,
exploit these innate regulatory mechanisms. It is not well-known how lipophiles, which bind at the periphery of
the protein, alter channel function and equilibrium between functional states. Such a molecular mechanism is
essential for the rational, structure-based design of new drugs targeting this family of channels. To address this
knowledge gap, the candidate will use a combination of innovative molecular dynamics (MD) techniques to
characterize state-dependent structural ensembles of prokaryotic pLGIC, ELIC (Erwinia ligand-gated ion
channel), and the human 7 nicotinic acetylcholine receptor (nAChR). Aim 1 will determine how the conformation
of the lipid-facing, fourth transmembrane (M4) helix varies with the functional state of the channel (i.e., resting,
activated, desensitized), using computational electrophysiology methods. Aim 2 will characterize the binding site
of docosahexaenoic acid (DHA), a polyunsaturated fatty acid, and how binding of DHA causes inhibition using
multiscale simulation and free energy calculations. This work will yield novel insight into state-dependent
dynamics of pLGICs as well as establish a molecular model of lipophilic allosteric modulation. This research will
be conducted under Dr. Wayland Cheng, an expert in pLGIC structure and function with a focus on lipid binding
and modulation, along with co-mentor, Dr. Grace Brannigan, an expert in computational biophysics with a focus
on MD method development and application to membrane proteins. An advisory committee comprised of Dr.
Alex Evers, an expert in anesthetic pharmacology, Dr. Baron Chanda, an expert in ion channel thermodynamics
and gating, and Dr. Jerome Hénin, an expert in free energy calculations, will aid in the scientific development of
the candidate. The research plan will allow the candidate to develop skills in free energy calculations and
computational electrophysiology, which will prepare him for a career in computational biophysics of ion channels.
In addition, involvement in career development activities during this award will prepare the candidate for
independence by the end of the award. The Department of Anesthesiology at Washington University in St. Louis,
a leader in academic anesthesiology, provides an excellent and supportive environment for ion channel research
and developm...

## Key facts

- **NIH application ID:** 10916479
- **Project number:** 5K08GM152844-02
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Mark Joseph Arcario
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $185,953
- **Award type:** 5
- **Project period:** 2023-09-01 → 2028-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10916479

## Citation

> US National Institutes of Health, RePORTER application 10916479, Unraveling how Lipophilic Modulators Alter pLGIC Function via Interactions with the M4 Transmembrane Helix (5K08GM152844-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10916479. Licensed CC0.

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