A Multi-Scale Approach to Model K⁺ Permeation Through the KcsA Channel

Area of Science:

• Biophysics
• Molecular Biology
• Ion Channel Function

Background:

• Potassium (K+) channels are vital for cellular function, enabling efficient K+ ion passage while excluding Na+ ions.
• The KcsA K+ channel structure, known for over 20 years, provides molecular insights into K+ permeation and selectivity.
• Recent studies suggest the K+ channel selectivity filter (SF) lacks water and can hold four adjacent K+ ions.

Purpose of the Study:

• To investigate the mechanism of K+ permeation through KcsA channels using a multi-scale approach.
• To determine stable ion configurations within the KcsA SF under physiological conditions.
• To develop a kinetic permeation model based on simulated ion configurations and experimental data.

Main Methods:

• Molecular dynamics (MD) simulations to identify stable K+ ion configurations in the KcsA SF.
• Continuum Bikerman-Poisson-Boltzmann modeling to validate MD findings, considering ion volume and dehydration.
• Kinetic permeation modeling using rate constants from molecular meta-dynamics simulations.

Main Results:

• MD simulations revealed K+ ions primarily occupy central SF sites (S2, S3) and channel entrances, with external and internal sites also occupied.
• S1 and S4 sites within the KcsA SF were consistently found to be unoccupied by K+ ions.
• The Bikerman-Poisson-Boltzmann model corroborated MD results, showing distinct K+ occupancy peaks at S2, S3, and entrances.
• A kinetic permeation model accurately reproduced experimental KcsA channel properties, including current-voltage and conductance-concentration relationships.

Conclusions:

• The identified equilibrium ion configuration in the KcsA SF is crucial for K+ permeation.
• The multi-scale approach successfully modeled K+ channel function, aligning simulation results with experimental observations.
• This study enhances understanding of the molecular mechanisms governing K+ ion selectivity and transport through ion channels.