Self-organized Models of Selectivity in Ca and Na Channels

TL;DR

This paper presents a simple, self-organized model using Monte Carlo simulations that explains the selectivity of Ca and Na channels across various solutions without relying on detailed crystal structures.

Contribution

It introduces a minimal pillbox model with adjustable parameters that captures ion-channel selectivity through self-organized structures determined by free energy minimization.

Findings

Model accurately predicts Na and Ca channel selectivity in diverse solutions.

Selectivity arises from induced fit and side chain flexibility.

Self-organized structures are key to understanding ion selectivity.

Abstract

A simple pillbox model with two adjustable parameters accounts for the selectivity of both DEEA Ca channels and DEKA Na channels in many ionic solutions of different composition and concentration. Only the side chains are different in the model of the Ca and Na channels. Parameters are the same for both channels in all solutions. 'Pauling' radii are used for ions. No information from crystal structures is used in the model. Side chains are grossly approximated as spheres. The predicted properties of the Na and Ca channels are very different. How can such a simple model give such powerful results when chemical intuition says that selectivity depends on the precise relation of ions and side chains? We use Monte Carlo simulations of this model that determine the most stable-lowest free energy-structure of the ions and side chains. Structure is the computed consequence of the forces in this model. The relationship of ions and side chains vary with ionic solution and are very different in simulations of the Na and Ca channels. Selectivity is a consequence of the 'induced fit' of side chains to ions and depends on the flexibility (entropy) of the side chains as well as their location. The model captures the relation of side chains and ions well enough to account for selectivity of both Na channels and Ca channels in the wide range of conditions measured in experiments. Evidently, the structures in the real Na and Ca channels responsible for selectivity are self-organized, at their free energy minimum. Oversimplified models are enough to account for selectivity if the models calculate the 'most stable' structure as it changes from solution to solution, and mutation to mutation.