Molecular computations on selectivity and permeation in ion channels and transporters

Molecular modeling in conjunction with molecular dynamics simulations is used to describe mechanisms of permeation and selectivity in the AE1 transporter and the L-type calcium channel. It is also used to propose a novel set of β-barrel structures for the antimicrobial peptide protegrin.; Protegrins are cystine-rich broad-spectrum antimicrobial peptides with 16–18 amino acid residues and a β-hairpin structure constrained by disulphide bonds. A set of β-barrel structures are proposed that might explain the cell permeablising effects and single channel formation observed in model bilayers with protegrin-1 (PG-1) and protegrin-3 (PG-3).; An “inverting basket” model for transport in the AE1 protein involving side chain conformational changes is described. The inverting basket is formed by the side chains of three putative key residues, two positively (Lys 826 and Arg 730) and one negatively (Glu 681) charged residue. These residues bind to an anion and shift from outward facing (C₀) to inward facing (C_i) conformation without significant backbone movements to transport an anion across the membrane. The barrier to inversion is composed of two major components: that of the anhydrous complex, referred to as a steric energy barrier, and a dehydration effect due to the removal of charges in the complex from water in the channel.; Applied Field Non Equilibrium Molecular Dynamics (AF NEMD) simulations of a model β-barrel channel with a flexible filter consisting of four glutamates (EEEE), and a homology model of the L-type calcium channel based on the KcsA crystal structure, provide a mechanism for the anomalous mole fraction effect (AMFE) observed in calcium channels. Ca2+ block of Na+ current is probably due to the glutamate side chains tetra-coordinating a single Ca2+ ion that not only occludes the permeation pathway but may also, by virtue of carboxylate positioning, prevent Na+ ions from entering the selectivity filter. Ca 2+ relief of Ca2+ block probably takes place by a combination of electrostatic repulsion between the permeant ions and stepwise changes in affinity mediated through glutamate side chain conformational changes.