Molecular Dynamics Simulations of Monolayers and Membranes with Phosphatidylinositol Bisphosphate

Abstract

Proper functionality of biological membranes depends on the regulation of lipid composition and localization. Spatial localization of molecules within the lipid bilayer depends on both steric effects due to their acyl chains and attractive or repulsive interactions between lipid headgroups, such as those mediated by the electrostatic charge of the lipid. Most eukaryotic lipids are zwitterionic or have a charge of −1 at physiological pH, but some lipids such as phosphatidylinositol bisphosphate (PtdInsP2) bear a net charge of −4. The ability of these highly charged lipids to interact with monovalent and divalent cations affects their spatial organization and temporal distribution on the cytoplasmic side of membranes. In turn, these lipids act as important effectors of apoptosis, inflammation, motility, and proliferation through their interactions with proteins at the membrane interface and transmembrane ion channels. In particular, PtdInsP2 is able to stabilize the open conformation of both eukaryotic potassium channels and those produced by bacteria, which normally lack PtdInsP2 lipids in their membrane. We hypothesize that in some settings PtdInsP2 acts by changing the physical-chemical properties of the membrane rather than by specific biochemical binding to proteins. To explore this hypothesis using molecular dynamics simulations, we completed a set of novel parameterizations at the MP2/6-31+G∗ level of theory for the three PtdInsP2 isoforms in several geometries and protonation states. Here we report that there are key differences in the way calcium and magnesium interact with the PtdInsP2 headgroup and that divalent cations likely influence the propensity of the lipids to form clusters.