Ion channels are molecular machines that act as the gateway to the extracellular world. They manage the flow of ions through the cellular membrane, modulating biological function. Hyperpolarization-activated cyclic nucleotide-gated 2 (HCN2) ion channels play a fundamental role in electric signaling in nerves, muscles, and synapses; however, their function and gating mechanism are not well understood.Through collaboration between experimental and computational methods, this study brings insight into the mechanism of the HCN2 channel activation by determining the cAMP-free (apo) structure and the changes from the cAMP-bound (holo) to the apo state. We used a novel computationalmethod, self-guided Langevin dynamics (SGLD), in conjunction with transition metal ionF�rster resonance energy transfer (tmFRET). SGLD enhances the low-frequency motion and accelerates the protein conformational search by using guiding forces on the molecular system. We started from the holo state structure, resolved by X-Ray crystallography, and used five sets of constraints determined from tmFRET distances to guide the protein into its apo state. The simulations enabled sampling of conformations along the state transition, giving insight into the occurring structural changes and determining a strong candidate for the HCN2 apo structure.

Determining the apo state structure of the HCN2 ion channel through collaboration between   computational simulations and transition metal ion FRET

248th National Meeting (2014)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.