A permeation theory for single-file ion channels: one- and two-step models

Area of Science:

• Biophysics
• Computational Biology
• Ion Channel Physiology

Background:

• Ion channel permeation mechanisms are complex, with existing models often failing to capture experimental behavior.
• Molecular dynamics (MD) simulations have suggested one-step models, but these do not align with typical experimental observations of Ohmic behavior at low voltages.

Purpose of the Study:

• To determine the optimal number of steps required to model ion channel permeation.
• To compare one- and two-step permeation models against experimental data and MD simulations.
• To develop an improved theoretical framework for ion channel permeation.

Main Methods:

• Fitting a one-step knock-on model to existing MD simulation data.
• Comparing a two-step association/dissociation (A/D) model with experimental permeation data for MaxiK and Shaker potassium channels.
• Developing and fitting an asymmetric variant of the A/D model to Shaker potassium channel data.
• Proposing a new theoretical framework using a one-dimensional permeation coordinate.

Main Results:

• The one-step model successfully explained MD simulation data but not real channel behavior.
• The two-step A/D model showed strong consistency with MaxiK channel experiments.
• The asymmetric A/D model accurately predicted Shaker channel behavior, including negative voltage data, based on positive voltage fits.
• The A/D model provides a framework for predicting channel occupancy and elementary steps.

Conclusions:

• A two-step association/dissociation model provides a more accurate representation of ion channel permeation than one-step models.
• The developed asymmetric A/D model and theoretical framework offer a quantitative link between MD simulations and experimental observations.
• This work advances the understanding of ion transport through channels and suggests new analysis methods.