Will it Permeate? Predicting Ion Channel Ion Selectivity, Permittivity and Block Mechanisms

Abstract

Modeling permeation of ions through an open transmembrane channel remains a difficult problem in theoretical biophysics. In most general terms a successful approach requires a faithful representation of an ion interaction with water, the channel protein, and other ions in solution, as well as a transport model for ion diffusion through the channel at a variety of applied voltages and salt concentrations. The process of ion permeation occurs over distances of hundred angstroms, and involves time-scale spanning from picoseconds to micro- or, even, milliseconds. In the last two decades a significant progress was achieved in both aspects of the problem: i) improving modeling of ion-protein interactions at short time-scales via empirical force-field employing molecular dynamics simulations, as well as ii) developing an ion-diffusion formalisms for long-time-scale ion motion at various voltages. In this talk I will describe a general hierarchical approach we developed for modeling ion permeation, in which information about ion - protein interactions can be supplied to a generalized electro-diffusion model (PNP) in the form of a Potential of Mean Force (PMF) of an ion in the channel (Mamonov et al. 2003). A generalized PNP to include a soft channel wall (SIP-PNP) (Simakov and Kurnikova, JPC2010) is a simplified model suitable for wider ion channels. Example applications, and limitations of the methods at both atomistic and continuum level of the modeling hierarchies will also be provided. I will also discuss our recent progress in modeling divalent cation permeation and blocking of a model pore of the NMDA receptor, which presents additional challenges to the theory of ion channel permeation (Kurnikov and Kurnikova, JPC 2015; Mesbahi et al. 2016).