# Molecular characterization of the influenza hemagglutinin mediated membrane fusion

> **NIH NIH R15** · UNIVERSITY OF ARKANSAS AT FAYETTEVILLE · 2020 · $422,578

## Abstract

PROJECT SUMMARY
Influenza hemagglutinin (HA) serves as a model system for the study of protein mediated membrane fusion.
It is the most important virulence factor for influenza viruses and is potentially a very attractive target for
novel therapeutic agents. Successfully targeting the inhibition of pH-induced large-scale conformational
changes that lead to membrane fusion could effectively prevent host cell infection. Antiviral agents
targeting other viral proteins are currently used to treat infections only after the appearance of symptoms.
Given that HA is the canonical type I glycoprotein, mechanistic studies of HA would contribute to our
understanding of the functional mechanisms of other viral fusogens as well. Our long-term goal is to
develop a computational framework for the rational design of novel therapeutic agents targeting the
conformational rearrangements that drive the influenza HA-mediated membrane fusion process. Our
overall objective here is to accurately describe, at an atomic and thermodynamic level, the conformational
and structural dynamics of HA under physiological conditions and in the presence of candidate drugs to
decipher the mechanism of HA activation and inhibition due to pH change and drug binding, respectively.
While current paradigm in biomolecular simulation studies is dominated by simplistic models such as
coarse graining (for large-scale conformational changes) and docking (for drug-protein interaction) and the
more accurate and reliable all-atom molecular dynamics (MD) simulations are limited to relatively short
timescales, we propose to use microsecond-level all-atom MD simulations in conjunction with statistical
mechanics based enhanced sampling techniques to provide a detailed, reliable account of the HA mediated
membrane fusion mechanism and its interactions with candidate drugs. The rationale for the proposed
research is that, if the molecular basis of HA-mediated membrane fusion is better understood, we can design
more potent therapeutic agents to combat influenza viruses. The proposed research will shed light on the
conformational landscape of a major influenza virulence factor, establishing a robust rational framework
for the design of novel therapeutic agents that can inhibit protein-mediated membrane fusion and prevent
influenza viral infections. This project will provide graduate and particularly undergraduate students at the
University of Arkansas with opportunities to work in an interdisciplinary area of biomedical research.

## Key facts

- **NIH application ID:** 10047161
- **Project number:** 1R15GM139140-01
- **Recipient organization:** UNIVERSITY OF ARKANSAS AT FAYETTEVILLE
- **Principal Investigator:** Mahmoud Moradi
- **Activity code:** R15 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $422,578
- **Award type:** 1
- **Project period:** 2020-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10047161

## Citation

> US National Institutes of Health, RePORTER application 10047161, Molecular characterization of the influenza hemagglutinin mediated membrane fusion (1R15GM139140-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10047161. Licensed CC0.

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