# Deciphering the relationship between structure, dynamics and function in helical bundle proteins

> **NIH NIH R35** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2023 · $718,047

## Abstract

Project Summary/Abstract
 This proposal combines work on viral ion channels and de novo protein design. Our work on the M2
proton channel from influenza A virus focuses on the mechanism of inhibition and proton movement through
the channel. M2 is also the target of the amantadine class of influenza drugs, and most isolates of influenza A
virus are now amantadine-resistant. Crystallography, computation and 2DIR will be used to interrogate the
mechanism and aid in design of drugs that inhibit M2 in amantadine-resistant strains of the virus. In parallel,
we will expand our studies to examine the mechanism of conduction and inhibition of the E-proteins from
coronaviruses, which have structures and functions largely similar to M2.
 De novo protein design provides a means to test and refine our understanding of protein structure and
function. We are developing computational methods to design proteins that bind small molecules such as
drugs and metalloporphyrins. We are also designing membrane proteins to elucidate the principles by which
they fold and function. To probe the mechanisms of highly selective proton conduction proteins, we are
designing proton-selective channels that test a hypothesis that networks of water molecules (water wires) can
form dynamically and transiently through apolar stretches of the proton conduction pathway in proteins. The
water wires would allow conduction of protons but not large hydrated alkali metal ions such as K+ or Na+. We
also are engaged in design of proteins that bind to and transport nutrients such as amino acids across
membranes, and devising screens to test them in vivo.

## Key facts

- **NIH application ID:** 10703499
- **Project number:** 5R35GM122603-07
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** WILLIAM DEGRADO
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $718,047
- **Award type:** 5
- **Project period:** 2017-05-01 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10703499

## Citation

> US National Institutes of Health, RePORTER application 10703499, Deciphering the relationship between structure, dynamics and function in helical bundle proteins (5R35GM122603-07). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10703499. Licensed CC0.

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