Pore formation in complex biological membranes: torn between evolutionary needs

Abstract The primary function of biological membranes is to enable compartmentalization among cells and organelles. Loss of integrity by the formation of membrane pores would trigger uncontrolled depolarization or influx of toxic compounds, posing a fatal thread to living cells. How the lipid complexity of biological membranes enables mechanical stability against pore formation while simultaneously allowing ongoing membrane remodeling is largely enigmatic. We performed molecular dynamics simulations of eight complex lipid membranes including the plasma membrane and membranes of the organelles ER, Golgi, lysosome, and mitochondrion. To quantify the mechanical stability of these membranes, we computed the free energies for nucleating a transmembrane pore as well as the line tension along the rim of open pores. Our simulations reveal that complex biological membranes are overall remarkably stable, however with the plasma membrane standing out as exceptionally stable, which aligns with its crucial role as a protective layer. We observe that sterol content is the main regulator for biomembrane stability, and that lateral sorting among lipid mixtures influences the energetics of membrane pores. A comparison of 25 model membranes with varying sterol content, tail length, tail saturation, and head group type shows that the pore nucleation free energy is mostly associated with the lipid tilt modulus, whereas the line tension along the pore rim is determined by the lipid intrinsic curvature. Together, our study provides an atomistic and energetic view on the role of lipid complexity on biomembrane stability. Significance statement Biomembranes have evolved to fulfill seemingly conflicting requirements. Membranes form a protective layer against bacterial or viral infection and against external mechanical and toxic stress, thus requiring mechanical stability. However, membranes are furthermore involved in ongoing remodeling for homeostasis, signaling, trafficking, and morphogenesis, necessitating a high degree of plasticity. How the chemical diversity of membranes, comprising hundreds of lipid species, contributes to enable both stability and plasticity is not well understood. We used molecular simulations and free energy calculations of pore formation in complex biomembranes to reveal how mechanical and geometric properties of lipids as well as lateral lipid sorting control the integrity of complex membranes.