Asymmetric Interplay Between K⁺ and Blocker and Atomistic Parameters From Physiological Experiments Quantify K⁺...

Area of Science:

• Biophysics
• Molecular Biology
• Computational Chemistry

Background:

• Modulating ion channel activity with blockers provides insights into drug mechanisms and ion transport.
• Understanding ion channel function is crucial for various physiological processes and therapeutic interventions.

Purpose of the Study:

• To investigate the interplay between ions and blocker release kinetics in the selectivity filter (SF) of potassium (K+) channels.
• To develop a quantitative model for predicting blocker release rate constants based on ion occupation probabilities.

Main Methods:

• Kinetic modeling of single-channel currents to determine voltage-dependent ion occupation probabilities in the SF.
• Development of a quantitative expression relating blocker release rate constants to ion occupation probabilities.
• 3D reference interaction site model (3D RISM) calculations to corroborate model findings.

Main Results:

• A quantitative model was derived, accurately predicting blocker release rate constants using only two adjustable ion-blocker interaction parameters.
• The K+ ion occupation probability in the SF was found to be independent of the blocker, attributed to strong ion-carbonyl attraction.
• The model holds true under both symmetric and asymmetric ionic conditions.

Conclusions:

• Potassium channel blocker release kinetics can be simplified to a few system-specific parameters.
• The pore-independent interaction between K+ ions and blockers suggests generalizability to other potassium channels.
• This research enhances understanding of ion transport mechanisms and informs the design of novel channel modulators.