Down-State Model of the KvAP Full Channel

Abstract

Voltage-gated potassium (Kv) channels have at least two distinct conformations, an “up” state, corresponding to the open/activated state of the channel, and a “down” state, corresponding to the resting state of the channel. Kv channels are tetramers that consist of a central pore domain (PD) and four peripheral voltage-sensing domains (VSDs) that respond to changes in the transmembrane (TM) potential. The PD opens and closes via mechanical coupling to the VSDs, which undergo large conformational changes as the TM potential changes. The molecular mechanism of these changes is poorly understood, because the Kv crystal structures reported to date are exclusively in the up state. We have recently reported a down-state model of the isolated VSD of KvAP that is consistent with existing experimental data. Based on this down-state model, we have now generated a down-state model for the KvAP full channel using targeted molecular dynamics. We used the end point of an equilibrated simulation of the KvAP full channel in the up state as a starting point and four symmetrically arranged down-state VSDs as targets. The PD was unconstrained during the simulation. Preliminary results suggest that, as expected, steric interactions between the S4-S5 linker and the intracellular half of S6 result in a measurable narrowing of the pore. We compare our model to the closed-state structure of the KcSA channel (2001, Science 280: 69), which consists of a Kv-homologous PD but no VSD, and to the Kv1.2 mammalian channel down-state model of Pathak et al (2007, Neuron 56: 124). This work is supported by NIH grants GM74637 and GM86685 and NSF grant CHE-0750175, and we are grateful for the allocation of computer time on the NSF-supported Teragrid resources provided by the Texas Advanced Computing Center.