Analysis and quantification of lipid bilayer bending energetics in atomic detail and under applied curvature.

Abstract

Changes in the morphology of biological membranes (cells, organelles, or vesicles) can and do occur at multiple length scales. However, the underlying causes are quite diverse, ranging from lipid composition to the action of membrane-bound proteins. The extent to which each biological factor controls membrane shape remains largely unknown. Quantification of membrane bending free-energy can be achieved by molecular-dynamics (MD) simulation, provided that enhanced-sampling schemes are used to overcome limitations in length- and time-scale. In this work, the free-energy required to reversibly deform a membrane was computed explicitly and in atomistic detail for multiple mixed-composition bilayers, of sizes up to 2,000 lipids. The contributions of specific molecular properties (lipid orientation, chain flexibility, and hydrophobic hydration) were also quantified. Results are not only in excellent agreement with giant-vesicle measurements, but also explain their apparent inconsistency with experiments done at the nanometer scale (Ashkar et al, 2021; Nagle et al, 2021). By identifying the specific mechanisms responsible for changes in membrane stiffness, our findings explain more clearly how a protein-lipid interface and global membrane shape can affect one another.