A Molecular Dynamics Investigation of Lipid Bilayer Perturbation by PIP2

Abstract

Phosphoinositides like phosphatidylinositol 4,5-bisphosphate (PIP(2)) are negatively charged lipids that play a pivotal role in membrane trafficking, signal transduction, and protein anchoring. We have designed a force field for the PIP(2) headgroup using quantum mechanical methods and characterized its properties inside a lipid bilayer using molecular dynamics simulations. Macroscopic properties such as area/headgroup, density profiles, and lipid order parameters calculated from these simulations agree well with the experimental values. However, microscopically, the PIP(2) introduces a local perturbation of the lipid bilayer. The average PIP(2) headgroup orientation of 45 degrees relative to the bilayer normal induces a unique, distance-dependent organization of the lipids that surround PIP(2). The headgroups of these lipids preferentially orient closer to the bilayer normal. This perturbation creates a PIP(2) lipid microdomain with the neighboring lipids. We propose that the PIP(2) lipid microdomain enables the PIP(2) to function as a membrane-bound anchoring molecule.

Dual Effect of Phosphatidyl (4,5)-Bisphosphate PIP2 on Shaker K+ Channels

“…The simulation used the CHARMM22-CMAP force field with torsional cross-terms for the protein (34), CHARMM36 for the POPC phospholipids (35), and the CHARMM-compatible parameters for PIP 2 developed in the group of Pr. Osman (36). The simulations were performed on the SGI ALTIX ICE Machine JADE at the CINES supercomputer center (Montpellier, France).…”

The Cytosolic GH Loop Regulates the Phosphatidylinositol 4,5-Bisphosphate-induced Gating Kinetics of Kir2 Channels

“…We replaced PIP 2 with its analog diC1 PIP 2 , which has two methyl groups. The atomic charges of the PIP 2 head group were taken from the ab initio calculations by Lupyan and colleagues (26). A grid map was generated for the Kir2.2 full-length structure using CHNOP (i.e.…”

Combined in vitro and in silico approaches to the assessment of stimulant properties of novel psychoactive substances – The case of the benzofuran 5-MAPB

“…The simulations were carried out as described in (Khelashvili et al, 2015b) using ACEMD software (Harvey et al, 2009). Briefly, the simulations employed the all-atom CHARMM27 force field for proteins with CMAP corrections was used (Brooks et al, 2009) as well as the CHARMM36 force field for lipids (Klauda et al, 2010), the TIP3P water model, and the CHARMM-compatible force-field parameter set for PIP 2 lipids (Lupyan et al, 2010). The PME method for electrostatic calculations was used, along with 4fs integration time-step with standard mass repartitioning procedure for hydrogen atoms implemented in ACEMD.…”