Ion Behaviour in the HCN1 Channel Selectivity Filter

Abstract

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels belong to the voltage-gated cation channel superfamily and are responsible for the generation of Ih in cardiac and neuronal cells. Despite the overall structural similarity to voltage-gated potassium (Kv) channels, they show much lower selectivity for K+ over Na+ ions. This increased permeability to Na+ ions is a critical to its role in depolarizing cellular membranes. They are also one of the only known proteins to select between Na+ and Li+ ions, making HCNs semi-selective channels. Here we investigate the unique selectivity properties of HCN channels using molecular dynamics simulations. Our simulations suggest that the HCN1 pore is very flexible and dilatated compared to Kv channels and that there is only one stable ion binding site within the selectivity filter. We also observe that ion co-ordination and hydration differ within the selectivity filter of HCN1 compared to Kv and CNG channels. Additionally, the co-ordination of K+ ions the carbonyl groups of the selectivity filter is more stable compared to Na+ and Li+ ions, which may explain the channel's distinct selectivity properties.