The Interaction of Phospholipase A2 with a Phospholipid Bilayer: Coarse-Grained Molecular Dynamics Simulations

Abstract

A number of membrane-active enzymes act in a complex environment formed by the interface between a lipid bilayer and bulk water. Although x-ray diffraction studies yield structures of isolated enzyme molecules, a detailed characterization of their interactions with the interface requires a measure of how deeply such a membrane-associated protein penetrates into a lipid bilayer. Here, we apply coarse-grained (CG) molecular dynamics (MD) simulations to probe the interaction of porcine pancreatic phospholipase A2 (PLA2) with a lipid bilayer containing palmitoyl-oleoyl-phosphatidyl choline and palmitoyl-oleoyl-phosphatidyl glycerol molecules. We also used a configuration from a CG-MD trajectory to initiate two atomistic (AT) MD simulations. The results of the CG and AT simulations are evaluated by comparison with available experimental data. The membrane-binding surface of PLA2 consists of a patch of hydrophobic residues surrounded by polar and basic residues. We show this proposed footprint interacts preferentially with the anionic headgroups of the palmitoyl-oleoyl-phosphatidyl glycerol molecules. Thus, both electrostatic and hydrophobic interactions determine the location of PLA2 relative to the bilayer. From a general perspective, this study demonstrates that CG-MD simulations may be used to reveal the orientation and location of a membrane-surface-bound protein relative to a lipid bilayer, which may subsequently be refined by AT-MD simulations to probe more detailed interactions.

The 3-dimensional structure of a hepatitis C virus p7 ion channel by electron microscopy

“…The most representative CG monomer was converted into atomistic detail using the software Modeller v8 (http://www.salilab.org/modeller/), by using the positions of the CG backbone particles as templates for the positions of the alpha carbons (32,33). To obtain the best fitted atomistic model, we generated 1,000 atomistic models from the CG model, which were then filtered using the root mean square deviation of the backbone positions.…”

Systematic multiscale simulation of membrane protein systems

“…As an alternative step towards bridging CG simulations with molecular scale phenomena, a combined atomic-CG methodology has been developed [49,50] wherein a CG membrane protein self assembly simulation is used to generate a starting configuration for a conventional atomistic MD simulation. In this approach, the final configuration of the CG simulation is converted to an atomistic model, which is then used as the initial configuration for a conventional atomic MD simulation.…”

“…In this approach, the final configuration of the CG simulation is converted to an atomistic model, which is then used as the initial configuration for a conventional atomic MD simulation. This approach was applied to phospholipase A2 [49] and a hydrated influenza M2 channel–dipalmitoylphosphatidylcholine (DPPC) lipid bilayer system [50]. Within the context of Fig.…”

Location of Inhibitors Bound to Group IVA Phospholipase A2 Determined by Molecular Dynamics and Deuterium Exchange Mass Spectrometry

“…Extensive simulations of the phospholipase A 2 `s have been carried out. Most notably, Wee et al recently conducted a coarse-grained simulation of the pancreatic phospholipase A 2 , in which they demonstrate how the enzyme adheres to the lipid bilayer 40. Quantum mechanical methodologies have also been applied to the phospholipase system 41.…”