Unconventional Ion-Permeation Pathways in NaVAb and CavAb Channels from Molecular Simulations with Polarizable Force-Fields

Abstract

The availability of high-resolution structures for bacterial homologuesvariety of well-established force-fields firmly established that selective Na+ transport relies on the multi-ion permeation mechanisms with some substantial differences from a narrow-pore knock-on permeation detailed for K+ selective channels. However, binding of multiple ions into a crowded space common to selectivity filters pose a number of conceptual questions regarding role of local of Na+ and Ca2+ selective channels open an avenue for in-depth understanding of selective permeation mechanisms central to electrical signaling in excitable cells. A plethora of studies performed with classical Molecular Dynamics simulations techniques using a dielectric and polarization effects. Our recent work firmly established limits of applicability of the classical force-fields in studies of divalent ions binding to metalloprotein hosts. The energetics of Na+ interactions with protein hosts is captured considerably better by classical approximation. To establish detailed permeation mechanisms with explicit account for polarization effects, we performed MD simulations combined with QM computations for different mixtures of sodium, potassium, calcium ions permeating across Na+ selective (NaVAb) and Ca2+ selective (CavAb), channels. From 2D PMFs and QM ion-protein interaction energies, we reported significant changes in the permeation pathways of ions in these two models unravelling bases of selective transport in physiologically relevant ion channels. We proposed a different view on how the channels select ions, in a way that is clearly distinguishable from potassium-selective channels.