Targeting Cellular Organelles by Amphipathic Helices: Taking Advantage of Membrane Biophysics

Eukaryotic cells are characterized by a rich variety of membranes, that differ by both morphology and lipid composition. These membranes form the boundaries of the different cellular organelles, that can be selectively targeted by certain peripheral proteins to trigger specific signaling and trafficking pathways.Using atomistic molecular dynamics simulations and new analysis tools we have recently been able to understand at the molecular level how a family of membrane curvature sensors, the Amphipathic Lipid Packing Sensor (ALPS) motifs, can specifically bind to lipid bilayers that are abundant in lipid packing defects, such as those induced by membrane curvature.Since organelle membranes are identified by their characteristic lipid composition and geometrical shape, we resort to a coarse grained approach based on the MARTINI force field to quantify in a systematical way the effect of these two parameters on the statistical distribution of lipid packing defects in model membranes. This allows us to identify how the peculiar amino acid composition of different amphipathic helices modulates their preferential interaction with specific membranes by taking advantage of their unique physicochemical features.This microscopic understanding paves the way for the rational design of protein mutants able to selectively target subcellular compartments thanks to altered membrane binding properties.