Atomic-level simulation of current-voltage relationships in single-file ion channels

Area of Science:

• Biophysics
• Computational Biology
• Molecular Physiology

Background:

• Ion channels are crucial for physiological processes, but characterizing individual permeation events is difficult.
• Understanding ion conduction mechanisms in channels like KV1.2/2.1 is fundamental to physiology.

Purpose of the Study:

• To investigate K+ permeation through the KV1.2/2.1 channel using long all-atom simulations.
• To elucidate the mechanistic principles of ion conduction at the single-ion level.

Main Methods:

• Utilized long, all-atom simulations on special-purpose hardware to study K+ permeation.
• Simulated the KV1.2/2.1 voltage-gated potassium channel, including voltage-sensing domains.
• Performed complementary simulations on gramicidin A to compare ion recruitment mechanisms.

Main Results:

• Simulated permeation rates were lower than experimental rates, even at physiological voltages.
• Observed a "knock-on" permeation mechanism across all simulated voltages.
• Including voltage-sensing domains shifted the linear current-voltage regime closer to experimental voltages, but permeation rate remained underestimated.
• Reduced ion-selectivity filter interaction strength did not enhance conductance in KV1.2/2.1, unlike in gramicidin A.

Conclusions:

• Direct simulation of single-ion permeation provides physiological insight, despite the need for high voltages.
• Infrequent ion recruitment into the pore lumen limits the simulated permeation rate.
• The knock-on permeation mechanisms in KV1.2 and KcsA channels may differ.