# Computational Studies of Ion Channels

> **NIH NIH R01** · UNIVERSITY OF CHICAGO · 2021 · $504,763

## Abstract

C-type inactivation of K+ channels is a molecular process of great physiological significance. In the central
nervous system, it affects the firing patterns of neurons on the time-scale of seconds, and impaired/altered
inactivation leads to a variety of neurological disorders. In neurons the onset and duration of the conductive
state of voltage-gated K+ channels, which are directly modulated by the interplay of activation and inactivation,
underlie the action-potential firing rates. In the heart, the extremely fast C-type inactivation of the hERG
channel plays an important role in the repolarization of cardiac cells. Thus, understanding the molecular basis
of inactivation has a direct impact on human health. The pH-activated bacterial KcsA channel is a critically
important prototypical model system; there is strong evidence that the C-type inactivated state of this channel
is caused by a constriction of the selectivity filter. Our overarching hypothesis is that C-type inactivation is a
conformational change of the selectivity filter controlled by competing factors: local packing and hydrogen
bonding interactions establish the inherent thermodynamic stability of the conductive filter, while further
stabilization/destabilization is communicated via the allosteric coupling with the intracellular gate, or through-
space interactions of the pore domain with the voltage sensor in the case of voltage-activated channels. The
goal of the proposed research is to test our hypothesis and delineate the conformational plasticity of the
selectivity filter of K+ channels in molecular terms. This will be achieved by relying on a multidisciplinary
strategy that combines computational and experimental approaches. In aim 1, we will study the molecular
determinants of the activation/inactivation allosteric coupling in the KcsA channel. We will generate an
extensive Markov State Model (MSM) encompassing all the microscopic events of opening the intracellular
gate, ion conduction, and entry into inactivation on the basis of aggregate data from a large number of
unbiased MD trajectories in order to provide a complete computational paradigm of the activation/inactivation
gating process in KcsA. We will determine the X-ray structure of KcsA with engineered Shaker-like mutations
known to affect C-type inactivation and characterize these systems with MD. In aim 2, we will investigate the
structural polymorphism of the selectivity filter in chimeric bacterial channels built from the cationic NaK
channel and the calcium-activated cationic channel NaKTs channel. Finally, in aim 3, we will investigate the
molecular determinants of activation/inactivation in the voltage-gated K+ channels Shaker, Kv1.2 and hERG
using X-ray crystallography, functional measurements, and MD simulations.

## Key facts

- **NIH application ID:** 10113630
- **Project number:** 5R01GM062342-20
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** BENOIT ROUX
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $504,763
- **Award type:** 5
- **Project period:** 2001-01-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10113630

## Citation

> US National Institutes of Health, RePORTER application 10113630, Computational Studies of Ion Channels (5R01GM062342-20). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10113630. Licensed CC0.

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