TY - JOUR
T1 - The sliding-helix voltage sensor
T2 - Mesoscale views of a robust structure-function relationship
AU - Peyser, Alexander
AU - Nonner, Wolfgang
N1 - Funding Information:
Graduate Research Fellowship of the National Science Foundation to A.P. We thank Drs. Alice Holohean, Peter Larsson, and Karl Magleby for helpful discussions.
Funding Information:
Acknowledgments The authors are grateful for the support of the National Institutes of Health (grant GM083161) to W.N. and a
PY - 2012/9
Y1 - 2012/9
N2 - The voltage sensor (VS) domain of voltagegated ion channels underlies the electrical excitability of living cells. We simulate a mesoscale model of the VS domain to determine the functional consequences of some of its physical elements. Our mesoscale model is based on VS charges, linear dielectrics, and whole-body motion, applied to an S4 "sliding helix." The electrostatics under voltage-clamped boundary conditions are solved consistently using a boundary-element method. Based on electrostatic configurational energy, statistical-mechanical expectations of the experimentally observable relation between displaced charge and membrane voltage are predicted. Consequences of the model are investigated for variations of S4 configuration (a- and 310-helical), countercharge alignment with S4 charges, protein polarizability, geometry of the gating canal, screening of S4 charges by the baths, and fixed charges located at the bath interfaces. The sliding-helix VS domain has an inherent electrostatic stability in the explored parameter space: countercharges present in the region of weak dielectric always retain an equivalent S4 charge in that region but allow sliding movements displacing 3-4 e0. That movement is sensitive to small energy variations (\2 kT) along the path dependent on a number of electrostatic parameters tested in our simulations. These simulations show how the slope of the relation between displaced charge and voltage could be tuned in a channel.
AB - The voltage sensor (VS) domain of voltagegated ion channels underlies the electrical excitability of living cells. We simulate a mesoscale model of the VS domain to determine the functional consequences of some of its physical elements. Our mesoscale model is based on VS charges, linear dielectrics, and whole-body motion, applied to an S4 "sliding helix." The electrostatics under voltage-clamped boundary conditions are solved consistently using a boundary-element method. Based on electrostatic configurational energy, statistical-mechanical expectations of the experimentally observable relation between displaced charge and membrane voltage are predicted. Consequences of the model are investigated for variations of S4 configuration (a- and 310-helical), countercharge alignment with S4 charges, protein polarizability, geometry of the gating canal, screening of S4 charges by the baths, and fixed charges located at the bath interfaces. The sliding-helix VS domain has an inherent electrostatic stability in the explored parameter space: countercharges present in the region of weak dielectric always retain an equivalent S4 charge in that region but allow sliding movements displacing 3-4 e0. That movement is sensitive to small energy variations (\2 kT) along the path dependent on a number of electrostatic parameters tested in our simulations. These simulations show how the slope of the relation between displaced charge and voltage could be tuned in a channel.
KW - Computer simulation
KW - Ion channels
KW - Potassium channels
KW - Voltage gated
KW - Voltage sensor domain
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U2 - 10.1007/s00249-012-0847-z
DO - 10.1007/s00249-012-0847-z
M3 - Article
C2 - 22907204
AN - SCOPUS:84866552950
VL - 41
SP - 705
EP - 721
JO - European Biophysics Journal
JF - European Biophysics Journal
SN - 0175-7571
IS - 9
ER -