PIP2-Binding to an Open State Model of Kir1.1 Probed by Multiscale Biomolecular Simulations

Abstract

Phosphatidylinositol bisphosphate (PIP2) is an activator of mammalian inwardly rectifying potassium (Kir) channels. We have used multiscale simulations, via a sequential combination of coarse-grained and atomistic molecular dynamics to explore the interactions of PIP2 molecules within the inner leaflet of a lipid bilayer membrane with possible binding sites on both open and closed state models of the Kir1.1 (ROMK) channel. Coarse-grained simulations of the channels in PIP2-containing lipid bilayers identified the PIP2-binding site on each channel. These models of the PIP2-channel complexes were refined by conversion to an atomistic representation followed by molecular dynamics simulation in a lipid bilayer. The binding site in the closed state agrees with previous mutagenesis data of Kir1.1 as well as with previous modeling studies of related Kir channels. Intriguingly, analysis of the open state model reveals a differential interaction of PIP2 with key residues thought to be involved in PIP2 activation of the channel. These models will serve as a framework for the functional validation of PIP2 interactions with Kir1.1 and provide a fresh insight into how PIP2 stabilizes the open state of the Kir channel.