Proline-induced hinges in transmembrane helices: Possible roles in ion channel gating

A number of ion channels contain transmembrane (TM) alpa-helices that conta in proline-induced molecular hinges, These TM helices include the channel-f orming peptide alamethicin (Alm), the S6 helix from voltage-gated potassium (Kv) channels, and the D5 helix from voltage-gated chloride (CLC) channels . For both Aim and KvSG, experimental data implicate hinge-bending motions off the helix in an aspect of channel gating, We have compared the hinge-be nding motions of these TRI helices in bilayer-like environments by multi-na nosecond MD simulations in an attempt to describe motions of these helices that may underlie possible modes of channel gating. Aim is an alpha-helical channel-forming peptide, which contains a central kink associated with a G ly-x-x-Pro motif in its sequence, Simulations of Aim in a TM orientation fo r 10 ns in an octane slab indicate that the Gly-x-x-Pro motif acts as a mol ecular hinge, The 56 helix from Shaker Ky channels contains a Pro-Val-Pro m otif, Modeling studies and recent experimental data suggest that the KvSG h elix may be kinked in the vicinity of this motif. Simulations (10 ns) of an isolated KvSG helix in an octane slab and in a POPC bilayer reveal hinge-b ending motions. A pattern-matching approach was used to search for possible hinge-bending motifs in the TM helices of other ion channel proteins. This uncovered a conserved Gly-x-Pro motif in TM helix D5 of CLC channels. MD s imulations of a model of hCLC1-D5 spanning an octane slab suggest that this channel also contains a TM helix that undergoes hinge-bending motion, In c onclusion, our simulations suggest a model in which hinge-bending motions o f TM helices may play a functional role in the gating mechanisms of several different families of ion channels. (C) 2001 Wiley-Liss,Inc.