On the effect of applied lateral tension on the deformation energetics of biological membranes and the lipid dynamics within

Abstract A broad range of cellular functions involve transient or persistent changes in the morphology of lipid membranes, from the organellar to the molecular scale. By and large, the thermodynamics of protein-mediated remodeling, which often distort the membrane beyond its thermally accessible undulations, remain to be understood. Molecular Dynamics simulations enhanced by advanced sampling methods are uniquely suited to examine and quantitate these phenomena. Here, we leverage the Multi-Map simulation method to directly quantify how applied lateral tension impacts the energetics of both global and localized membrane perturbations induced extrinsically. We obtain free-energy profiles of curvature and thickness deformations with and without tension, which allow us to test the quadratic approximations of Helfrich-based continuum theories. We find that these continuum models are applicable up to ∼ 20 k B T, beyond which they under-estimate the free-energy cost of bending. However, we find that the effect of tension on these deformations is primarily driven by changes in the projected area of the membrane, and therefore consistent with continuum theory, even beyond 30 k B T. These changes outpace the effects of tension on lipid packing and diffusion, and importantly we find that tension levels preceding rupture (≤ 10 mN/m) do not impede complete lipid mixing. Finally, we investigate the free-energy landscapes of membrane thickness and lipid enrichment with a heterogeneous lipid composition and show that strong enrichment can be sustained even under steady exchange of the constituent lipid molecules. Statement of Significance Cells have evolved the ability to sense mechanical forces through specialized proteins embedded in their membranes. How exactly the membrane transduces these stimuli to the proteins therein has been unclear. Using state-of-the-art molecular simulations, we quantify the free-energy landscape of curvature and thickness deformations, varying either the applied lateral tension or lipid composition. Our results show that stretching a membrane does not exert an outward force on individual lipid molecules, even when these are biased toward a specific region of the membrane. Instead, lateral tension alters the membrane’s resistance to remodeling by penalizing changes in projected area, suggesting that membrane deformation energetics, and not lipid residence, drives the tension-responsive conformational changes in stretch-activated proteins.