CHARMM GUI Membrane Builder for oxidized phospholipid membrane modeling and simulation

Abstract

Oxidative stress leads to the production of oxidized phospholipids (oxPLs) that modulate the biophysical properties of phospholipid monolayers and bilayers. As many immune cells are responsible for surveilling cells and tissues for the presence of oxPLs, oxPL-dependent mechanisms have been suggested as targets for treating chronic kidney disease, atherosclerosis, diabetes, and cancer metastasis. This review details recent experimental and computational studies that characterize oxPLs' behaviors in various monolayers and bilayers. These studies investigate how the tail length and polar functional groups of OxPLs impact membrane properties, how oxidized membranes can be stabilized, and how membrane integrity is generally affected by oxidized lipids. In addition, for oxPL-containing membrane modeling and simulation, CHARMM-GUI Membrane Builder has been extended to support a variety of oxPLs, accelerating the simulation system building process for these biologically relevant lipid bilayers.

Keywords: Membrane; Molecular dynamics simulation; Molecular modeling; Oxidized phospholipid.

Figure 1.

Molecular structures of (a) KDdiA-PC and (b) KOdiA-PC. At left in each example are the structures obtained from all-atom molecular dynamics (MD) simulations of these oxPCs in a POPC bilayer membrane. The red spheres represent the oxygen atoms of the carboxylic acid functional groups at the end of the oxidized tails. (c) Simulated bilayer membrane composed of 20 mole % KDdiA-PC (cyan) in a background of POPC (gray). The water layers on both sides of the membrane are also shown. This system was built with CHARMM-GUI Membrane Builder.

Figure 2.

(a) Simulation snapshot of 20% KOdiA-PC system with a lipid composition of 50% POPC (purple), 20% KOdiA-PC (green), 30% cholesterol (cyan). (b) Z-density profiles of 20% KOdiA-PC system. (c) Voronoi tessellation of 20% KOdiA-PC system at 500 ns with the same lipid color scheme as in (a).

Figure 3.

Simulation snapshot of Lysosomal Integral Membrane Protein-2 (PDB id: 4Q4F) positioned above a POPC bilayer with 30% KOdiA-PC. Oxidized tail groups are highlighted in red. LIMP-2 is a member of the CD36 superfamily.