Abstract:
: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 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 that 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 construct 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, in which 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's 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.
journal_name
Biophys Jjournal_title
Biophysical journalauthors
Ke S,Ulmschneider MB,Wallace BA,Ulmschneider JPdoi
10.1016/j.bpj.2018.10.001subject
Has Abstractpub_date
2018-11-20 00:00:00pages
1920-1930issue
10eissn
0006-3495issn
1542-0086pii
S0006-3495(18)31113-5journal_volume
115pub_type
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