Molecular modeling predicts helix tilting in HCN channels during cAMP binding

Hyperpolarization-activated cyclic nucleotide-modulated (HCN) channels are believed to regulate the heartbeat. Binding of cAMP to a cytoplasmic binding domain (BD) increases probability of HCN channel opening; a C-linker region (helices A’-F’ and A) links the BD to the channel pore. The C-linker was proposed to move when cAMP binds the BD; I hypothesized a movement of D’- F’. I created two models of a cytoplasmic fragment from an "apo" HCN channel (without cAMP), one by comparative modeling and one by molecular dynamics. Compared to the crystal structure of the fragment with cAMP, both apo models showed D’ tilting, such that N-terminus gets farther and C-terminus closer to helix A. E’ translates parallel to the long axis of A from C- to N-terminus. Helix A did not change relative to the BD. Therefore when cAMP binds the HCN channel, the N-terminus of D’ is likely tilting towards the BD.