# Enabling physical stimuli in the study of structural dynamics: The sensory ion channels

> **NIH NIH DP1** · WEILL MEDICAL COLL OF CORNELL UNIV · 2020 · $1,186,500

## Abstract

Simon Scheuring, Weill Cornell Medicine
 Scientific Area : 6 MCB : Molecular and Cellular Biology / 5 IE : Instrumentation and Engineering
Project Summary/Abstract (30 lines of text):
In the recent years, we have seen tremendous progress in structural biology owing to breakthroughs in 3D-
crystallization methodology for X-ray diffraction and improved particle classification algorithms and the
development of direct electron detection for cryo-EM. As a result, membrane protein structure resolution is
now rather routine and progresses at a pace of almost 2 structures per week. To complement structures,
technologies like FRET, EPR and HDX give invaluable insights into the range of dynamics and kinetics of
conformational states. All experimental structural and dynamical techniques have however a blind spot:
they are poorly adapted to analyze proteins in response to physical stimuli such as force, temperature and
voltage. This is particularly regrettable for the case of sensory ion channels that process these physical
stimuli, because they are involved in some of the most crucial physiological functions and are implicated in
various pathologies. Another technique that is powerful to assess conformational dynamics is high-speed
atomic force microscopy (HS-AFM), this approach has two significant advantages: (i) it is also a structural
technique, meaning that it provides real-space real-time movies of molecules, and (ii) it operates under
physiological and changeable conditions. Thus, the first advantage allows to characterize the structure and
conformational changes of the channels at ~1nm lateral, ~0.1nm vertical and ~100ms temporal resolution.
While the second advantage opens the experimental tool to the application of external stimuli,
(bio)chemical and also, importantly, physical stimuli. In this project, we will develop novel extensions to HS-
AFM to take movies of the conformational response of sensory channels to such physical cues. We will
expose mechano-sensitive Piezo channels to force, temperature-sensitive TRPV channels to temperature-
sweeps, and voltage-gated K+ channels to the direct application of transmembrane voltage, and image the
structural changes of these proteins in response to such stimuli. This project will, on the one hand push the
limits of HS-AFM technologically and create novel operational modalities of it and such further establish this
rather new technology for a wide range of structure-function application in biomedical research, and on the
other hand be transformative for the structural biology of sensory ion channels by providing insights into
long-standing questions how these biological machines transform such physical stimuli into coordinated
conformational dynamics that ultimately lead to channel gating.

## Key facts

- **NIH application ID:** 9998844
- **Project number:** 5DP1AT010874-02
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Simon Scheuring
- **Activity code:** DP1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,186,500
- **Award type:** 5
- **Project period:** 2019-09-30 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9998844

## Citation

> US National Institutes of Health, RePORTER application 9998844, Enabling physical stimuli in the study of structural dynamics: The sensory ion channels (5DP1AT010874-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9998844. Licensed CC0.

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