Exploring the Molecular Dynamics of a Lipid-A Vesicle at the Atom Level: Morphology and Permeation Mechanism

Abstract

Lipid-A was previously shown to spontaneously aggregate into a vesicle via the hybrid particle field approach. We assess the validity of the proposed vesiculation mechanism by simulating the resulting lipid-A vesicle at the atom level. The spatial confinement imposed by the vesicle geometry on the conformation and packing of lipid-A induces significant heterogeneity of physical properties in the inner and outer leaflets. It also induces tighter molecular packing and lower acyl chain order compared to the lamellar arrangement. Around 5% of water molecules passively permeates the vesicle membrane inward and outward. The permeation is facilitated by interactions with water molecules that are transported across the membrane by a network of electrostatic interactions with the hydrogen bond donors/acceptors in the N-acetylglucosamine ring and upper region of the acyl chains of lipid-A. The permeation process takes place at low rates but still at higher frequencies than observed for the lamellar arrangement of lipid-A. These findings not only substantiate the proposed lipid-A vesiculation mechanism but also reveal the complex structural dynamics of an important nonlamellar arrangement of lipid-A.

Capric Acid and Myristic Acid Permeability Enhancers in Curved Liposome Membranes

“…Another cause for an apparent reduction in thickness could be undulations of the large membrane patches in the liposome systems. 67 Some analysis packages have been developed recently to measure APL and membrane thickness despite fluctuations, e.g., SuaVE 73,74 and LipidDyn. 75 We computed a set of parameters with the SuaVE package (results in Supporting Information) and found that this more advanced tool confirms that the thickness does decrease with curvature.…”