Role of the Interaction Motif in Maintaining the Open Gate of an Open Sodium Channel

TY - JOUR

T1 - Role of the Interaction Motif in Maintaining the Open Gate of an Open Sodium Channel

AU - Ke, Song

AU - Ulmschneider, Martin B.

AU - Wallace, B.A.

AU - Ulmschneider, Jakob P.

PY - 2018/10/4

Y1 - 2018/10/4

N2 - Voltage-gated sodium channels undergo transitions between open, closed and inactivated states, enabling regulation of the translocation of sodium ions across membranes. A recently-published crystal structure of the full length prokaryotic NavMs crystal structure in the activated open conformation (Sula et al, 2017) has revealed the presence of a novel motif consisting of an extensive network of salt bridges involving residues in the voltage sensor, S4-S5 linker, pore, and C-terminal domains. This motif has been proposed to be responsible for maintaining an open conformation which enables ion translocation through the channel. In this study we have used long-time molecular dynamics calculations without artificial restraints to demonstrate that the interaction network of full-length NavMs indeed prevents a rapid collapse and closure of the gate, in marked difference to earlier studies of the pore-only domain, in which the gate had to be restrained to remain open. Interestingly, a frequently discussed “hydrophobic gating” mechanism at nanoscopic level is also observed in our simulations, where the discontinuous water wire close to the gate region leads to an energetic barrier for ion conduction. In addition, we demonstrate the effects of in-silico mutations of several of the key residues in the motif on the open channel stability and functioning, correlating them with existing functional studies on this channel and homologous disease-associated mutations in human sodium channels; we also examine the effects of truncating/removing the voltage sensor and C-terminal domains in maintaining an open gate.

AB - Voltage-gated sodium channels undergo transitions between open, closed and inactivated states, enabling regulation of the translocation of sodium ions across membranes. A recently-published crystal structure of the full length prokaryotic NavMs crystal structure in the activated open conformation (Sula et al, 2017) has revealed the presence of a novel motif consisting of an extensive network of salt bridges involving residues in the voltage sensor, S4-S5 linker, pore, and C-terminal domains. This motif has been proposed to be responsible for maintaining an open conformation which enables ion translocation through the channel. In this study we have used long-time molecular dynamics calculations without artificial restraints to demonstrate that the interaction network of full-length NavMs indeed prevents a rapid collapse and closure of the gate, in marked difference to earlier studies of the pore-only domain, in which the gate had to be restrained to remain open. Interestingly, a frequently discussed “hydrophobic gating” mechanism at nanoscopic level is also observed in our simulations, where the discontinuous water wire close to the gate region leads to an energetic barrier for ion conduction. In addition, we demonstrate the effects of in-silico mutations of several of the key residues in the motif on the open channel stability and functioning, correlating them with existing functional studies on this channel and homologous disease-associated mutations in human sodium channels; we also examine the effects of truncating/removing the voltage sensor and C-terminal domains in maintaining an open gate.

KW - Voltage-gated Sodium Channel

KW - Molecular Dynamics Simulation

KW - Ion Translocation

KW - Channel Gating

U2 - 10.1016/j.bpj.2018.10.001

DO - 10.1016/j.bpj.2018.10.001

M3 - Article

SN - 0006-3495

JO - Biophysical Journal

JF - Biophysical Journal

ER -