Softening in two-component lipid mixtures by spontaneous curvature variance

The bending modulus of a lipid bilayer quantifies its mechanical resistance to curvature. It is typically understood in terms of thickness, e.g., thicker bilayers are stiffer. Here, we describe an additional and powerful molecular determinant of stiffness - the variance in the distribution of curvature sensitivity of lipids and lipid conformations. Zwitterionic choline and ethanolamine head-groups of glycero-phospholipids dynamically explore inter- and intra-species interactions, leading to transient clustering. We demonstrate that these clusters couple strongly to negative curvature, exciting undulatory membrane modes and reducing the apparent bending modulus. Three forcefields (Martini 2, Martini 3, and all-atom CHARMM C36) each show the effect to a different extent, with the coarse-grained Martini models showing the most clustering and thus the most softening. The theory is a guide to understanding the stiffness of biological membranes with their complex composition, as well as how choices of forcefield parameterization are translated into mechanical stiffness.