Atomistic Mechanism of Cation Permeation and Pore Voltage Sensitivity in Cyclic Nucleotide-Gated CNGA1 Ion Channel

Mammalian cyclic nucleotide-gated (CNG) ion channels play a fundamental role in signal transduction within the visual and olfactory sensory cells, converting external stimuli into electrical signals. Here, using large-scale atomistic molecular dynamics (MD) simulations under transmembrane voltages, we uncover the atomistic mechanism of monovalent cation permeation in the homotetrameric CNGA1 channel, involving hydrated cations in the selectivity filter. We propose that hydration fluctuations in the central gate region, driven by pore flexibility, are the underlying mechanism for excess single-channel conductance noise and characteristic single-channel flickering. Furthermore, we suggest an atomistic mechanism for intrinsic voltage sensitivity in the channel pore, mediated by allosteric coupling between the selectivity filter and the central cavity gate. Our study provides atomistic insights into non-selective cation permeation and voltage sensitivity of the CNGA1 channel pore that could not be resolved by static structural analysis alone.