Computational analysis of interactions between AMPA receptor and con-ikot-ikot conotoxin.

Abstract

Con-ikot-ikot (CII) is a toxin found in the venom of a marine snail Conus striatus, and the only conotoxin known so far to specifically target AMPA receptors (AMPAR) - a subtype of ionotropic glutamate receptors which are important for synaptic transmission and plasticity. It is small in size (∼20 kDa) and has a unique binding site, nestled between the layers of amino-terminal domains (ATDs) and ligand-binding domains (LBDs) of the receptor, which constitute its extracellular portion. Conotoxins and other animal-derived toxins have an established role as important molecular tools in studying various ion channels and some have already been repurposed as therapeutics, therefore we are interested in using CII to study AMPA receptors. In order to gain a better understanding of the interactions between con-ikot-ikot and AMPA receptors, we have performed all-atom molecular dynamics (MD) simulations of a complex of AMPAR extracellular domains (ATDs and LBDs) with glutamate and CII. Network analysis of the resulting MD simulation trajectories, performed using a residue interaction network (RIN)-based tool we are developing, recapitulates previously identified key residue interactions with ligand-binding domains (LBDs) of AMPARs, reveals novel interactions with the LBD layer and suggests interactions between CII and AMPAR amino-terminal domains (ATDs), making CII potentially the only known ligand to interact with AMPAR ATDs. Our new network analysis tool will allow the user to visualise and explore residue interaction networks of single frames, entire trajectories, or sets of trajectories. It will not only be a tool suitable for our needs in investigating the AMPAR/CII complex, but will also act as a general exploratory, hypothesis-generating tool that will be of interest for anyone looking to understand dynamic networks of protein-protein interactions.