# A new perspesective on ion conductance and structural dynamics of ion channels using 2D IR

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2020 · $354,053

## Abstract

Abstract
Patch clamp experiments performed since the 1970s have provided the timescales for the opening and closing
of ion channels. X-ray crystallography over the past 2 decades has yielded high-resolution structures of ion
channels. As yet, there are no direct experiments on channel dynamics or the effect of an applied voltage on ion
channel structures. In this proposal, we connect dynamics to structure by leveraging new technological advances
that enable two-dimensional infrared (2D IR) measurements on ion channels. The inherent time-resolution of 2D
IR spectroscopy is a few picoseconds – much faster than the millisecond motions of ion channels. Structural
resolution arises from couplings between the backbone carbonyl vibrations and electrostatic charges such as
ions. Residue-specific to domain-specific structural resolution is obtained with isotope labeling made routine by
semisynthesis procedures developed in the Valiyaveetil lab. And, 2D IR spectra can now be calculated very
accurately from short molecular dynamics trajectories, enabling a one-to-one comparison between experiment
and structure or proposed structural models. This combination of 2D IR, semisynthesis, and molecular dynamics
simulations permit a new perspective on ion channel structural dynamics. In this proposal, we address two
outstanding controversies in the potassium ion channel community. In Aims 1 and 2, we investigate a
controversial new model for ion permeation through the selectivity filter of KcsA and NaK, called the “hard-knock”
model. The hard-knock model appears to explain the X-ray data and all other existing measurements, even
though it is fundamentally at odds with the original “knock-on” model found in textbooks. In Aim 3, we voltage-
trigger the structural motions of the voltage sensing domain (VSD) of the KvAP channel, to investigate the
hypothesis that the essential TM4 helix in the VSD undergoes a conformational and/or hydrational change during
voltage gating, as previously proposed but never established by a direct structural or time-resolved
measurement. These aims provide new scientific insights into outstanding problems in the ion channel
community and establish a new technique for studying ion channel structural dynamics.

## Key facts

- **NIH application ID:** 10071850
- **Project number:** 1R01GM135936-01A1
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Francis Valiyaveetil
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $354,053
- **Award type:** 1
- **Project period:** 2020-08-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10071850

## Citation

> US National Institutes of Health, RePORTER application 10071850, A new perspesective on ion conductance and structural dynamics of ion channels using 2D IR (1R01GM135936-01A1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10071850. Licensed CC0.

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