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| Home > Publications database > Theoretical predictions of gating behavior for mutants of Shaker-type Kv channels from inter-domain energetics |
| Poster | FZJ-2014-04838 |
;
2014
Please use a persistent id in citations: http://hdl.handle.net/2128/9175
Abstract: A multiscale physical model of Shaker-type Kv channels is used to span from atomic-scale interactions to macroscopic experimental measures such as charge/voltage (QV) and conductance/voltage (GV) relations. The model [1] comprises the experimentally well-characterized voltage sensor (VS) domains described by four replications of an independent continuum electrostatic model under voltage clamp conditions [2, 3] and a hydrophobic gate controlling the flow of ions by a vapor lock mechanism [4], connected by a simple coupling principle derived from known experimental results and trial-and-error. The total Hamiltonian of the system is calculated from the computed configurational energy for each components as a function of applied voltage, VS positions andg ate radius, allowing us to produce statistical-mechanical expectation values for macroscopic laboratory observables over the full range of physiological membrane potentials (|V| ≤ 100 mV, in 1 mV steps). The Shaker QV and GV relations seen in Seoh et al. [5] are predicted by this model. With this approach, functional energetic relations can be decomposed in terms of physical components, and thus the effects of modifications in those elements can be quantified. We find that the total work required to operate the gate is an order of magnitude larger than the work available to the VS, and that the the experimentally observed bistable gating is due to the VS slide-and-interlock behavior. The same model was systematically applied to VS charge mutants (Seoh et al. [5]). The QV and GV relations can be qualitatively predicted and the associated effects on functional domains determined. Additional features such as surface charges become significant for the pathological cases. Our engineering approach clearly elucidates that both normal function and mutant changes are electrostatic in nature.[1] Alexander Peyser, Dirk Gillespie, Roland Roth, and Wolfgang Nonner. Domain and inter-domain energetics underlying gating in Shaker-type Kv channels. Accepted: Biophys J,2014. doi:10.1016/j.bpj.2014.08.015.[2] Alexander Peyser and Wolfgang Nonner. Voltage sensing in ion channels: Mesoscale simulations of biological devices. Phys Rev E StatNonlin Soft Matter Phys, 86: 011910, Jul 2012. doi:10.1103/PhysRevE.86.011910.[3] Alexander Peyser and Wolfgang Nonner. The sliding-helix voltage sensor: mesoscale views of a robust structure-function relationship. Eur Biophys J, 41:705–721,2012. doi:10.1007/s00249-012-0847-z.[4] Roland Roth, Dirk Gillespie, Wolfgang Nonner, and Robert E. Eisenberg. Bubbles, gating, and anesthetics in ion channels. Biophys J, 94(11):4282–4298,2008. doi:10.1529/biophysj.107.120493.[5] Sang-Ah Seoh, Daniel Sigg, Diane M. Papazian, and Francisco Bezanilla. Voltage-sensing residues in the S2 and S4 segments of the Shaker K+ channel. Neuron, 16 (6):1159–1167, 1 June1996. doi:10.1016/S0896-6273(00)80142-7.[6] Stephen B. Long, Xiao Tao, Ernest B. Campbell, and Roderick MacKinnon. Atomic structure of a voltage-dependent K+ channel in a lipid membrane-like environment. Nature, 450(7168):376–382,2007. doi:10.1038/nature06265.
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