# Angstrom-scale structural dynamics of a potassium channel

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2024 · $425,802

## Abstract

Project Summary
 Our long-term goal is to understand the mechanism of a class of protein molecules in cell membranes,
which enable ions to flow in or out of cells and thereby generate vital cellular electric signals. The knowledge
regarding the mechanisms of these proteins, called ion channels, form the essential scientific basis for us to
pursue the pathogenic mechanisms of certain disease processes and to develop therapies. Generally, the
functions of channels are regulated by specific signaling processes, and what underlie these regulations are
protein-conformational changes. The goal of this proposal is to further develop a fluorescence-polarization
microscopy method to accurately track in three-dimensions (3D) a fluorophore attached to a protein on an
angstrom-and-millisecond scale, and to apply this method to the investigation of conformational dynamics of
the bacterial Trk channel, which is a new target to combat certain antibiotics-resistant enterobacteria.
 Structural biology has yielded abundant protein structures. However, a full understanding of a protein
molecule must include both its spatial and temporal features. We thus need to go beyond studying a protein's
static structures on an atomic scale and study its dynamics on angstrom-and-millisecond scales. Thus far, the
experimental information about protein dynamics is often lacking, due to the absence of relatively general
methods for reliably tracking rapid angstrom-scale conformational changes of a protein. Typically, such small
changes can be reliably and quantitatively resolved only with structural techniques such as crystallography or
Cryo-EM, which, unfortunately, lack time resolution. Light microscopy may be time-resolved but its spatial
resolution had remained generally too low to resolve angstrom-scale protein conformational changes.
 Recently, we have successfully resolved protein conformational changes occurring on millisecond-and-
angstrom scales by examining emission polarization of a fluorophore attached to a protein under examination.
With a state-of-the-art fluorescence-polarization microscope and an analytic package that we put together, we
have achieved an effective angle resolution of 5-10°. Over this range, a rotational motion of a protein molecule
of an average size would cause a 1.7 - 3.5 Å change in the chord distance. Here, we will continue to develop
this method and demonstrate its applicability beyond the molecule used to develop the method, besides
acquiring important knowledge in biomedical science. With this method, we will determine the energetics and
kinetics of the protein-conformational changes underling the Trk channel's function. Integrating the resulting
dynamic information with available structural information will yield a mechanistic spatiotemporal 4D model that
accounts for the channel's behaviors on millisecond-and-angstrom scales. Success of our study will transform
the way that we investigate the dynamic mechanisms of proteins, and accelerat...

## Key facts

- **NIH application ID:** 10846801
- **Project number:** 5R01GM055560-25
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** ZHE LU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $425,802
- **Award type:** 5
- **Project period:** 1997-05-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10846801

## Citation

> US National Institutes of Health, RePORTER application 10846801, Angstrom-scale structural dynamics of a potassium channel (5R01GM055560-25). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10846801. Licensed CC0.

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