A computational docking and molecular dynamics simulations study to identify the putative phosphoinositide binding site(s) of HCN channels
Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are a type of voltage gated ion channels that control rhythmic activity and synaptic plasticity in the heart and brain. These channels allow K+ and Na+ ions to pass, thereby creating an inward current upon hyperpolarization of the membrane. Due to its unusual biophysical properties, this current is called funny « If» or hyperpolarization « Ih » current. Abnormalities in Ih current are associated with arrythmia and neurological disorders including epilepsy. Different molecules are found to modulate this current. Experimental results have shown that lipids play a role in shifting the voltage dependence of HCN channels to more positive, or depolarized voltages. Both endogenous and exogenous phospholipid phosphatidylinositol 4,5-bisphosphate, or PI(4,5)P2, regulates HCN channels by shifting the opening of the channel to a more depolarized voltage. This modulation is postulated to be through direct interaction of PI(4,5)P2 with the HCN channel. Here, we use molecular dynamics and docking to explore and identify the binding site through analysis of the contacts and stability of the hydrogen bonds involved in phosphoinositide molecules and HCN channel interaction. We propose LYS and ARG residues of the HCN domain and S3 to be key residues in the binding site through which phosphoinositide molecules can potentially activate the channel.
HCN Channel Ih current Phosphoinositide Molecular Dynamics Docking