Electromechanics of lipid-modulated gating of Kv channels

Abstract

Experimental studies reveal that anionic lipid POPA and non-phospholipid cholesterol inhibit the gating of voltage-sensitive potassium (Kv) channels at 5-10% molar concentrations. Intriguingly, other anionic lipids similar to POPA, like POPG, have minimal impact on the gating of the same channels for reasons that remain obscure. Our long-timescale atomistic simulations show that POPA preferentially solvates the voltage sensor domains of Kv channels by direct electrostatic interactions between the positively charged arginine and negatively charged phosphate groups. Cholesterol solvates the voltage sensor domains through CH-{pi} interactions between the cholesterol rings and the aromatic side chains of phenylalanine and tyrosine residues. A continuum electromechanical model predicts that POPA lipids may restrict the vertical motion of voltage-sensor domain through direct electrostatic interactions, while cholesterol may oppose the radial motion of the pore domain of the channel by increasing the mechanical rigidity of the membrane. The electromechanical model predictions are consistent with measurements of the activation curves of Kv channels for various lipids. The atomistic simulations also suggest that the solvation due to POPG is much weaker likely due to its bigger head-group size. Thus the channel activity appears to be tied to the local lipid environment, allowing lipids to regulate channel gating in low concentrations.