Properties of Lipid Models of Lung Surfactant Containing Cholesterol and Oxidized Lipids: A Mixed Experimental and Computational Study

Abstract

We introduce and study a multicomponent lipid film mimicking lipid composition of the human lung surfactant. It consists of phospholipids with various lipid headgroups and tail saturation. Furthermore, it includes cholesterol and oxidized lipids. Langmuir trough and fluorescence microscopy experiments are combined with fully atomistic molecular dynamics simulations. The considered lipid mixtures form complex interfacial films with properties modulated by lateral compression. Cholesterol laterally condenses, and oxidized lipids laterally expand the films; both types of molecules increase film miscibility. Oxidized lipids also alter the lipid−water interface enhancing film hydration; this effect can be partially reversed by cholesterol. Regarding presentation of different chemical moieties toward the aqueous subphase, the zwitterionic phosphatidylcholine groups dominate at the lipid−water interface, while both the negatively charged phosphatidylglycerol and hydroxyl group of cholesterol are less exposed. The investigated synthetic lipid-only mimic of the lung surfactant may serve as a basis for further studies involving nonlipid pulmonary surfactant components.

Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design

“…Simulations of lipid bilayers containing products of lipid oxidations have found a decrease in permeability for the case of oxysterols [550] and tail oxidized phosphatidylcholine [481]. From the standpoint of pharmaceutical research, the most interesting are studies of membranes that form a boundary with an extracellular environment, including bacterial membranes [415,[610][611][612][613][614][615][616], the stratum corneum, i.e., the most external layer of the skin [617][618][619][620][621][622][623][624][625][626], membranes present in the eyes [557,[627][628][629][630][631], and the ocular mucous membrane [632], or lung surfactant monolayers [263,558,[633][634][635][636][637][638]. Specifically, MD simulations have been used in studies of enhancer effects on the permeability of the stratum corneum (e.g., [544]).…”

Understanding the Functional Properties of Lipid Heterogeneity in Pulmonary Surfactant Monolayers at the Atomistic Level

“…Molecular simulations are often helpful in resolving such aspects down to the atomistic level (Enkavi et al, 2019). However, previous simulation studies on multi-component monolayers are relatively scarce (Baoukina et al, 2007a(Baoukina et al, ,b, 2008(Baoukina et al, , 2012(Baoukina et al, , 2014Baoukina and Tieleman, 2011) with only a few studies performed using atomistic models (Javanainen et al, 2010;Olzyńska et al, 2020). While previous simulations have generated a lot of insight to better understand the behavior of surfactant monolayers, they have been haunted by the insufficiently accurate description of the physical behavior of the lipids at the interface, that, in turn, was largely due to insufficient quality of water models in describing phenomena at water-monolayer-air interfacial regions (Baoukina et al, 2007b;Vega and De Miguel, 2007;Lamberg and Ollila, 2015;Javanainen et al, 2017a).…”

Simulated Breathing: Application of Molecular Dynamics Simulations to Pulmonary Lung Surfactant

“…Olzy'nska et al investigated a system of DPPC:POPC:POPG:cholesterol (0.50:0.25:0.15:0.1) using both experimental and simulation-based data [93]. With the replacement of 10% POPC by Poxno-PC, there was an expansion of the film as the oxidized tails reorientate to associate with the hydrophilic region, consistent with the work by Stachowicz-Ku'snierz et al Contrarily, the addition of cholesterol leads to a condensation of fluid lipid films, and can buffer the influence of oxidized lipids by incorporating itself into the void created by the truncated tails [93]. This unique behavior of cholesterol to limit oxidative stress is a prime example of the value that molecular dynamics offers to explore the interworking of PS.…”