Tissue injury and cell death lead to inflammation and the production of reactive oxygen species (ROS) that cause oxidative stress. ROS are also by products of normal cellular respiration processes. Among many products of oxidative stress are oxidized phospholipids (oxPLs), in particular the phospholipids that make up cellular membranes or the surface of high and low density lipoprotein (HDL and LDL) particles. The hydrophobic fatty acid tails of unsaturated phospholipids are susceptible to oxidation reactions that render them polar through the addition of hydroxide, peroxide, aldehyde, carboxylic acid, and other functional groups [1]. Lipids containing polyunsaturated fatty acid (PUFA) tails are particularly susceptible to oxidation and are more prevalent in eukaryotic than prokaryotic membranes [2]. Some important examples of unsaturated phosphatidylcholines (PCs) are 1-palmitoyl-2-linoleoyl-sn-glycero-3-phosphocholine (PLPC) and 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (PAPC). These PCs can undergo reactions to generate a number of different oxidized PC (oxPC) products, such as KOdiA-PC and KDdiA-PC [2], which are shown in Figure 1a and b. The reaction mechanisms to generate various oxPCs and other oxPLs are reviewed elsewhere [3]. The oxPCs generated from PLPC and PAPC are similar in that their sn-1 position has a palmitoyl fatty acid tail, but they differ in the chain length of oxidized fatty acid at the sn-2 position. Crucially, these oxPCs and other oxPLs modulate the biophysical properties of phospholipid monolayers and bilayers [4, 5, 6, 7, 8, 9]. The polar functional groups of oxPL tails cause them to leave the hydrophobic core of the membrane bilayer and emerge into the membrane-water interface or aqueous environment, creating short “whiskers” that protrude from the membrane [10]. The protrusion of tail groups is observed in the simulated lipid bilayer membrane shown in Figure 1c. In this system, built with CHARMM-GUI Membrane Builder [11, 12, 13], 20 mol % KDdiA-PC is included in a bilayer membrane composed of POPC. It is readily apparent that the carboxylic acid functional groups on the oxidized tails extend into the aqueous milieu to create short whiskers above the membrane interface. These protruding whiskers are postulated to be a trigger of the immune system's response to oxidative stress [14].

The innate immune system is responsible for surveilling cells and tissues for the presence of oxPLs [15]. The scavenger receptor CD36 is one of the key proteins involved in recognition of oxPLs, and it is found on the surface of many immune cells, including monocytes, macrophages, and dendritic cells [16]. Specifically, CD36 recognizes oxPCs in membranes and on the surface of oxLDL particles [17]. And the recognition event is dependent on both the headgroup and the oxidized moieties of the lipids. Binding of CD36 to oxPC initiates lipid uptake and/or phagocytosis by macrophages along with the activation of inflammatory pathways [18]. When macrophages internalize large amounts of lipids, they become laden with excess lipid and become foam cells [19]. Altering the progression of macrophages to foam cells via CD36-dependent mechanisms has been suggested as therapies for chronic kidney disease [20], atherosclerosis [21], diabetes [22], and cancer metastasis [23].

The impact of oxPLs on the biophysical properties of membranes have been investigated by a variety of different techniques, both experimental and computational. These approaches have revealed a number of changes to membrane properties induced by oxPLs, including but not limited to a decrease in membrane thickness, an increase in membrane permeability, and that oxPLs adopt an altered structural configuration where the oxidized moiety protrudes into the aqueous media surrounding the lipid bilayer (Figure 1). In this article, we will highlight some of the recent advances in the study of oxPLs, particularly those where computational studies have shed light on the biophysical impacts of phospholipid oxidation on membrane structure and function. Additionally, we will describe a new molecular modeling tool based on CHARMM-GUI Membrane Builder that increases the scope and accessibility of membrane simulations with oxPLs.