Role of membrane lipids for the activity of pore forming peptides and proteins.

Bilayer lipids, far from being passive elements, have multiple roles in polypeptide-dependent pore formation. Lipids participate at all stages of the formation of pores by providing the binding site for proteins and peptides, conditioning their active structure and modulating the molecular reorganization of the membrane complex. Such general functions of lipids superimpose to other particular roles, from electrostatic and curvature effects to more specific actions in cases like cholesterol, sphingolipids or cardiolipin. Pores are natural phenomena in lipid membranes. Driven by membrane fluctuations and packing defects, transient water pores are related to spontaneous lipid flip-flop and non-assisted ion permeation. In the absence ofproteins or peptides, these are rare short living events, with properties dependent on the lipid composition of the membrane. Their frequency increases under conditions of internal membrane disturbance of the lipid packing, like in the presence of membrane-bound proteins or peptides. These latter molecules, in fact, form dynamic supramolecular assemblies together with the lipids and transmembrane pores are one of the possible structures of the complex. Active peptides and proteins can thus be considered inducers or enhancers of pores which increase their probability and lifetime by modifying the thermodynamic membrane balance. This includes destabilizing the membrane lamellar structure, lowering the activation energy for pore formation and stabilizing the open pore structure.