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A Molecular Dynamics Investigation of Lipid Bilayer Perturbation by PIP2 Dmitry Lupyan Mount Sinai School of Medicine

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A Molecular Dynamics Investigation of Lipid Bilayer Perturbation by PIP2 Dmitry Lupyan Mount Sinai School of Medicine Virginia Commonwealth University VCU Scholars Compass Physiology and Biophysics Publications Dept. of Physiology and Biophysics 2010 A Molecular Dynamics Investigation of Lipid Bilayer Perturbation by PIP2 Dmitry Lupyan Mount Sinai School of Medicine Mihaly Mezei Mount Sinai School of Medicine Diomedes E. Logothetis Mount Sinai School of Medicine, Virginia Commonwealth University Roman Osman Mount Sinai School of Medicine Follow this and additional works at: http://scholarscompass.vcu.edu/phis_pubs Part of the Medicine and Health Sciences Commons From The iopB hysical Journal, Lupyan, D., Mezei, M., Logothetis, D.E., et al., A Molecular Dynamics Investigation of Lipid Bilayer Perturbation by PIP2, Vol. 98, Page 240. Copyright © 2010 Biophysical Society. Published by Elsevier Inc. Reprinted with permission. Downloaded from http://scholarscompass.vcu.edu/phis_pubs/25 This Article is brought to you for free and open access by the Dept. of Physiology and Biophysics at VCU Scholars Compass. It has been accepted for inclusion in Physiology and Biophysics Publications by an authorized administrator of VCU Scholars Compass. For more information, please contact [email protected]. 240 Biophysical Journal Volume 98 January 2010 240–247 A Molecular Dynamics Investigation of Lipid Bilayer Perturbation by PIP2 Dmitry Lupyan,† Mihaly Mezei,† Diomedes E. Logothetis,†‡ and Roman Osman†* †Department of Structural and Chemical Biology, Mount Sinai School of Medicine, New York, New York; and ‡Department of Physiology and Biophysics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia ABSTRACT Phosphoinositides like phosphatidylinositol 4,5-bisphosphate (PIP2) 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 PIP2 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 PIP2 introduces a local perturbation of the lipid bilayer. The average PIP2 headgroup orientation of 45 relative to the bilayer normal induces a unique, distance-dependent organization of the lipids that surround PIP2. The headgroups of these lipids preferentially orient closer to the bilayer normal. This perturbation creates a PIP2 lipid microdomain with the neighboring lipids. We propose that the PIP2 lipid microdomain enables the PIP2 to function as a membrane-bound anchoring molecule. INTRODUCTION Phosphatidylinositol is a lipid molecule found in the cyto- PIP-adhesion proteins have a specialized domain through solic leaflet of the cell plasma membrane and in the which they bind PIPs with various degrees of selectivity. membranes of several intracellular organelles. Its phosphor- Though a number of structures of different PIP-interacting ylated derivatives are known as phosphoinositides (PIPs) (1). domains have been solved (free and in complex), the basis PIPs have two hydrocarbon tails, arachidonate and stearate, of protein-PIP stereoselectivity remains elusive (9). which are connected through a glycerol group to the inositol At this time, a combination of biochemical, diffraction, headgroup. Three phosphorylation sites on the 3, 4, and 5 and spectroscopic techniques are widely used to study PIP2 positions of the inositol ring give rise to seven distinct synthesis, aggregation/sequestration, cell localization, and combinations of mono-, bis-, and tris-phosphorylated prod- interactions with proteins. These techniques provide a wealth ucts. Inside the cell, phosphoinositide turnover is tightly of information about the macroscopic properties of PIP2 controlled by metabolic regulatory enzymes such as special- (10). Computational techniques, on the other hand, can be ized kinases, phosphatases, and phospholipases. Defects in used to explore the microscopic behavior of PIPs. In this phosphoinositide metabolism are associated with disorders work, we present atomic-resolution results from molecular such as cancer, cardiovascular disease, and autoimmune dynamics (MD) simulations of PIP2 in a lipid bilayer. dysfunction (2,3). Because the data extracted from such studies closely agrees Depending on the cell type, PIPs constitute ~1–2% of the with the available experimental data, MD simulation is total phospholipids in the plasma membrane. Despite their a good tool for studying various aspects of lipid behavior low membrane content, PIPs are known to spatially sequester that are not easily measurable through experimental work into PIP-enriched rafts, and thus, the local concentration of (11–15). PIPs varies dramatically (4,5). Inside the cell, the products Several studies have used MD simulations to explore the of phosphoinositide metabolism are key membrane signaling interactions of PIP2 with specific residues of peptides and molecules that play an important role in numerous intracel- proteins (16–20), and one study explores the dynamic differ- lular signaling pathways. For example, the most abundant ences between PIP2 and phosphatidylinositol 3,4,5-trisphos- PIP is PI(4,5)P2 (commonly abbreviated as PIP2 (Fig. 1 A)), phate inside the bilayer (21). Another study suggests that the which has long been considered to act as a ubiquitous second lipids that surround PIP2 also play a significant role in messenger and as a precursor to other second messengers, protein interactions; it is thought that these lipids facilitate such as diacylglycerol (DAG), D-myo-inositol 1,4,5-tri- penetration of PIP2-interacting proteins into the bilayer by sphosphate (IP3), and phosphatidylinositol 3,4,5-trisphos- forming additional hydrogen bonds with the protein (18). phate (PIP3)(3,6,7). More recently, it was also suggested In this work, we investigate the interaction of PIP2 with that PIP2 may have some intrinsic catalytic activity (8). neighboring lipids and its organization within the lipid Another widely recognized functional role of PIP2 and other bilayer. We first design force field parameters for the phos- PIPs is as substrates for a variety of PIP-effector proteins. All phoinositide headgroup to enable further investigation with MD simulation. To understand how PIP2 carries out such a wide variety of biological functions, we simulate PIP2 Submitted June 15, 2009, and accepted for publication September 29, 2009. inside the lipid bilayer and characterize its molecular, *Correspondence: [email protected] structural, and dynamic properties. We also show and Editor: Reinhard Lipowsky. Ó 2010 by the Biophysical Society 0006-3495/10/01/0240/8 $2.00 doi: 10.1016/j.bpj.2009.09.063 PIP2 Perturbation of Lipid Bilayer 241 A B C FIGURE 1 (A) Heavy atom represen- tation of a PIP2 lipid molecule. The inositol headgroup is red; phosphates are yellow, the glycerol connecting the headgroup to the acyl chains is cyan, and the arachidonate and stearate acyl chains are green and blue, respectively. (B) Schematic of the PIP2 headgroup with the nomenclature of the atom names. To change the phosphorylation state of the phosphoinositides, the force fields have been designed such that a hydroxyl group (blue) can be replaced by a phosphate group (magenta). (C) Partial charges correspond to atom names in B. describe how PIP2 induces the formation of a PIP2 lipid for the system’s equilibration profile). The temperature was kept constant microdomain by reorganizing the neighboring lipids in a at 330 K by using Langevin dynamics, and a Nose´-Hoover Langevin piston unique way. We speculate that the formation of such was used for pressure control at 1 bar (27,28). The simulations were run at temperatures above the DPPC gel-liquid transition phase (29,30). microdomains is an important property of PIP2, allowing it to act as a membrane-anchoring molecule. 2D radial distribution function The two-dimensional radial distribution function (g2D(r)) available in COMPUTATIONAL METHODS GROMACS was used to characterize the lateral radial distribution of lipids Lipid system setup in the bilayer plane (31). In this method, the counting and distances are calculated in the x-y plane, disregarding the z axis. The coordinates of the preequilibrated 1,2-dipalmitoyl-sn-glycero-3-phos- phocholine (DPPC) membrane patch at 323.15 K were obtained from the website of Dr. Jeffrey B. Klauda, with an initial box size of 48.0  48.0  Lipid pulling 66.118 A˚ (22). The membrane system contained 72 DPPC lipid molecules To show that adhesion forces that resist the extraction of a lipid molecule (36 in each leaflet), to which 150 mM of KCl and ~3400 TIP-3 water mole- from a bilayer are greater for PIP than for a typical lipidlike DPPC, we cules were added. To prepare the simulations containing a phosphoinositide, 2 performed an atomic force microscopy (AFM)-type pulling through MD a single DPPC molecule in the pure DPPC membrane patch was replaced by simulations. Steered molecular dynamics (SMD) has been employed to a phosphatidylinositol molecule, and two phosphate groups were added to simulate the extraction of a PIP and DPPC lipid molecules from DPPC bila- positions 4 and 5 on the inositol headgroup. Furthermore, additional coun- 2 yers. Previous works have shown that SMD results agree well with the terions were added to neutralize the system. The average size of all the experimental AFM data (32–34). In SMD simulations, a macromolecular systems was ~20,000
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