Title: Molecular Dynamics Studies of Ion Channel Regulation
Abstract: Ion channels are proteins embedded in the cell membrane that allow the passive diffusion of ions along the electrochemical gradient. Voltage, pH, ligands and lipids can act as key regulators of their functions. Along with specific lipid-protein interactions, the physiochemical properties of the membrane, such as hydrophobic thickness, my also influence ion channel activity by stabilizing or destabilizing specific conformations. We present atomic-scale molecular dynamics simulations of the wild-type and E71A mutant of KcsA, a prokaryotic potassium channel in membranes of differing thickness, in support of experimental studies.
Voltage-gated ion channels open and close in response to the potential drop across the lipid bilayer they are imbedded in. These channels contain a specialized voltage-sensing domain (VSD) with a mobile helix (S4) that contains regularly-spaced, positively-charged residues. The movement of the S4 through the membrane results in a transient current called the gating charge, which is sometimes experimentally measureable, and can also be predicted using computer simulation. Despite identical sequences of the S4 helices and the linker connecting the VSD to the pore domain (S4-5), the four human isoforms of hyperpolarization-activated cyclic-nucleotide gated (HCN) channels (HCN1-4) are known to activate with different voltage dependencies and gating kinetics. Here we begin to examine the molecular details of S4 movement in HCN channels through molecular dynamics simulations based on homology models. Although the gating charge of the sea urchin isoform HCN channel (spHCN) is estimated to be very small compared to that of other Kv channels, we show that this is possible even with a similar displacement of the S4 helix. Additionally, we have calculated the gating charges of the four human isoforms, which have been experimentally unobtainable to date.
Cm-Bio 2-9 Callahan