In an effort to delineate how cholesterol protects membrane structure under oxidative stress conditions, we monitored the changes to the structure of lipid bilayers comprising 30 mol% cholesterol and an increasing concentration of Class B oxidized 1-palmitoyl-2-oleoylphosphatidylcholine (POPC) glycerophospholipids, namely, 1-palmitoyl-2-(9'-oxo-nonanoyl)-sn-glycero-3-phosphocholine (PoxnoPC), and 1-palmitoyl-2-azelaoyl-sn-glycero-3-phosphocholine (PazePC), using atomistic molecular dynamics simulations. Increasing the content of oxidized phospholipids (oxPLs) from 0 to 60 mol% oxPL resulted in a characteristic reduction in bilayer thickness and increase in area per lipid, thereby increasing the exposure of the membrane hydrophobic region to water. However, cholesterol was observed to help reduce water injury by moving into the bilayer core and forming more hydrogen bonds with the oxPLs. Cholesterol also resists altering its tilt angle, helping to maintain membrane integrity. Water that enters the 1-nm-thick core region remains part of the bulk water on either side of the bilayer, with relatively few water molecules able to traverse through the bilayer. In cholesterol-rich membranes, the bilayer does not form pores at concentrations of 60 mol% oxPL as was shown in previous simulations in the absence of cholesterol.

Department of Physics University of Helsinki P O Box 64 00014 Helsinki Finland Department of Physics Tampere University of Technology P O Box 692 33101 Tampere Finland

Department of Physics University of Helsinki P O Box 64 00014 Helsinki Finland Department of Physics Tampere University of Technology P O Box 692 33101 Tampere Finland MEMPHYS Center for Biomembrane Physics University of Southern Denmark Odense Denmark

Institute of Complex Systems Structural Biochemistry Forschungszentrum Jülich 52425 Jülich Germany CEITEC Central European Institute of Technology Masaryk University Kamenice 753 5 625 00 Brno Czech Republic

Institute of Complex Systems Structural Biochemistry Forschungszentrum Jülich 52425 Jülich Germany Institute of Theoretical and Computational Chemistry Heinrich Heine University Düsseldorf Universitätsstrasse 1 40225 Düsseldorf Germany

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