Biophysical Society Conference | Tahoe 2022

Molecular Biophysics of Membranes

Tuesday Speaker Abstracts

POTENTIALS OF MEAN FORCE OF BIOMEMBRANE DEFORMATION Giacomo Fiorin 1,2 ; José D Faraldo-Gómez 1 ; 1 National Institutes of Health, National Heart, Lung and Blood Institute, Bethesda, MD, USA 2 National Institutes of Health, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA Lipid membranes are known to undergo macroscopic deformations as the cell's morphology changes, as well as microscopic ones caused by individual proteins. It is also increasingly recognized that a membrane's shape actively contributes to the function of the proteins bound to it. However, quantifying the extent of this coupling requires connecting different length scales and physical effects. Toward this goal, we introduced a method to measure the free-energy of lipid bilayer deformations from enhanced-sampling molecular dynamics simulations. The bilayer need not be homogeneous or symmetric, and may be atomically detailed or coarse-grained. A set of three-dimensional density maps is used to define a “reaction pathway” for the membrane leaflets, and the associated free-energy profile is computed directly from intermolecular forces and configurational sampling. While the likelihood of certain membrane configurations is artificially enhanced, no further restraints are placed on the internal motions of the membrane, thus allowing for fully-reversible thermodynamic sampling. This method, called Multi-Map, was applied alongside standard equilibrium MD to atomistic bilayers of different compositions and sizes. A diversity of microscopic effects is shown to contribute to membrane bending, and thus the same stiffness constant can account for different effects in different lipids. This notion can rationalize otherwise surprising changes in the membrane's stiffness between synthetic compositions and more physiological ones, for example in phospholipid-cholesterol mixtures. The data gathered also shed light on a recent controversy regarding the effect of cholesterol on membrane mechanics (Ashkar et al, PNAS 2021; Nagle et al, PNAS 2021). Given the increasing significance of biomembrane energetics at the molecular scale, techniques based on direct simulation are in a unique position to complement theory and experiment precisely in those cases where quantification is most challenging.

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