Ion channel selectivity through ion-modulated changes of selectivity filter pK_a values

Area of Science:

• Biophysics
• Molecular Biology
• Computational Chemistry

Background:

• Bacterial voltage-gated sodium channels utilize a selectivity filter (SF) with four glutamate residues to control ion passage.
• Existing models for ion selectivity involve steric effects and ion-induced conformational changes.

Purpose of the Study:

• To propose and investigate an alternative mechanism for ion selectivity in bacterial sodium channels.
• To explore the role of ion-triggered shifts in the pKa values of SF glutamates.

Main Methods:

• Free-energy calculations using molecular dynamics simulations on the Na_vMs channel.
• Analysis of pKa values of SF glutamates in different ionic solutions (Na+ vs. K+).
• Calculation of ion conductance through different protonation states of the SF glutamates.

Main Results:

• pKa values of SF glutamates are higher in K+ solutions compared to Na+ solutions.
• This pKa shift is attributed to the increased population of protonated, 'dunked' conformations in K+.
• Conductance decreases significantly with increasing protonation of glutamate residues, with the deprotonated state being most conductive.

Conclusions:

• Ion-triggered shifts in glutamate pKa values represent a significant mechanism for bacterial sodium channel selectivity.
• This mechanism favors more conductive states for Na+ and less conductive states for K+.
• The proposed mechanism aligns with experimentally observed pH dependence of selectivity in similar channels.