| Abstract: | Structure and dynamics of voltage-gated ion channels, in particular the motion ofthe S4 helix, is a highly interesting and hotly debated topic in currentmembrane protein research. It has critical implications for insertion andstabilization of membrane proteins as well as for finding how transitions occurin membrane proteins—not to mention numerous applications in drugdesign. Here, we present a full 1 µs atomic-detail molecular dynamicssimulation of an integral Kv1.2 ion channel, comprising 120,000 atoms. Byapplying 0.052 V/nm of hyperpolarization, we observe structural rearrangements,including up to 120° rotation of the S4 segment, changes inhydrogen-bonding patterns, but only low amounts of translation. A smallerrotation (∼35°) of the extracellular end of all S4 segments ispresent also in a reference 0.5 µs simulation without applied field,which indicates that the crystal structure might be slightly different from thenatural state of the voltage sensor. The conformation change uponhyperpolarization is closely coupled to an increase in 310 helixcontents in S4, starting from the intracellular side. This could support a modelfor transition from the crystal structure where the hyperpolarizationdestabilizes S4–lipid hydrogen bonds, which leads to the helixrotating to keep the arginine side chains away from the hydrophobic phase, andthe driving force for final relaxation by downward translation is partlyentropic, which would explain the slow process. The coordinates of thetransmembrane part of the simulated channel actually stay closer to the recentlydetermined higher-resolution Kv1.2 chimera channel than the starting structurefor the entire second half of the simulation (0.5–1 µs).Together with lipids binding in matching positions and significant thinning ofthe membrane also observed in experiments, this provides additional support forthe predictive power of microsecond-scale membrane protein simulations. |
