Selectivity filter mutations shift ion permeation mechanism in potassium channels

Area of Science:

• Biophysics
• Molecular Biology
• Structural Biology

Background:

• Potassium (K+) channels exhibit remarkable conductance and selectivity.
• Two proposed mechanisms explain K+ permeation: direct knock-on (water-free) and soft knock-on (water-mediated).
• Previous studies suggested soft knock-on based on crystal structures of mutated KcsA channels.

Purpose of the Study:

• To investigate and differentiate between the direct and soft knock-on mechanisms of K+ channel permeation.
• To test the interpretation that mutations in KcsA's selectivity filter support the soft knock-on mechanism in wild-type channels.

Main Methods:

• Molecular dynamics simulations of the KcsA channel and its mutants (G77, T75).
• Analysis of ion-ion and ion-water configurations within the selectivity filter during permeation.

Main Results:

• Wild-type KcsA channels exhibit water-free direct knock-on permeation.
• Mutations induce conformational changes, leading to K+ and water co-permeation (soft knock-on characteristics).
• Mutated channels show reduced conductance and impaired K+ selectivity compared to wild-type.

Conclusions:

• Full dehydration of potassium ions is crucial for the high conductance and selectivity of K+ channels.
• Mutations at critical points in ion channel pathways can nonintuitively alter permeation mechanisms.
• The study highlights the importance of dynamic simulations in understanding ion channel function.