Elucidating the mechanical properties of asymmetric membranes by direct derivation of their energetics.

The asymmetry between the two leaflets of a plasma membrane (PM) is widely accepted as an essential condition for most PM-associated biochemical processes. However, recent work has also shown that asymmetric bilayers can be significantly stiffer upon bending than symmetric ones, suggesting that the same asymmetry may hinder the ability of the PM to remodel itself. Here, we address this issue by combining all-atom molecular dynamics (MD) simulations with an enhanced sampling scheme that explicitly induces membrane deformations to quantify their free-energy cost. Examining small asymmetric POPC/DOPC bilayers, we find that a small density imbalance between the leaflets increases their bending rigidity compared to bilayers with minimal imbalance, or to symmetric bilayers of the same two lipids. This result is consistent with recently proposed theoretical models that identify differential stress as the main source of stiffening in asymmetric membranes. The first-principles approach used in this study is broadly applicable to other types of membrane, enabling further exploration of the interplay between asymmetry and curvature, or the simulation of specific biological conditions of the PM.