Selectivity Filter Dynamics Define Ion Conductance and Selectivity Differences in CNG and HCN Channels

Area of Science:

• Biophysics
• Molecular Biology
• Ion Channel Physiology

Background:

• Cyclic nucleotide-gated (CNG) and hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are crucial for cellular electrical signaling.
• These channels share sequence similarity but differ in ion conductance, selectivity, and voltage dependence.
• Understanding these differences is key to their diverse physiological roles.

Purpose of the Study:

• To directly compare the ion conduction mechanisms of HCN and CNG channels.
• To elucidate the structural and dynamic determinants of differential ion selectivity and conductance.
• To provide a mechanistic basis for channel function and guide future channel design.

Main Methods:

• Microsecond-timescale atomistic molecular dynamics (MD) simulations.
• Utilized the K+-selective channel MthK as a reference.
• Analysis of ion conduction pathways and selectivity filter dynamics.

Main Results:

• Simulations accurately reproduced experimental electrophysiology data.
• Distinct selectivity filter architectures and dynamics were identified as key differences.
• These filter properties directly explain variations in ion conductance and K+ selectivity.

Conclusions:

• Structural and dynamic features of selectivity filters dictate ion permeation properties.
• Provides a mechanistic understanding of HCN and CNG channel functional divergence.
• Enables rational design of novel cation channels with specific properties.