Intermolecular interactions of membrane destabilizing peptides

Biological membranes are complex liquid-crystalline fluid materials of orientationally ordered proteins, peptides and lipids. The physical and structural properties of biological membranes are not only influenced by the type and composition of lipids, but also by the proteins/peptides within the membranes. For example, proteins and peptides can mediate membrane destabilization, which is an essential process for cell-to-cell membrane fusion, vesicle transport, antimicrobial activity, and virus proliferation. Therefore, a thorough analysis of membrane/protein interactions has broad implications for molecular cell biology.The mechanisms of membrane destabilization by peptides are not well understood. For example, it has been suggested that antimicrobial peptides (AMPs) could destabilize membranes by forming a carpet on the surface or holes within the membrane. It is not clear from the secondary structure or the amino acid sequence why one mode is preferred over the other. Other peptides with similar secondary structure, such as the competence stimulating peptides or type I antifreeze proteins, do not penetrate or destabilize membranes. In fact, antifreeze proteins seem to stabilize membranes. Another example is fusion peptides, which are very effective at destabilizing model membranes and causing lipid mixing - a presumed precursor to membrane fusion. The fusion peptides p14 and p15 from the fusion associated small transmembrane protein family are anchored to the membrane via an N-terminal myristoyl group. The p14 peptide, like all other fusion peptides, is slightly hydrophobic and is suspected to surface associate with the target membrane. The p15, on the other hand, is atypically hydrophilic, and apart form the N-terminal, has been shown not to strongly interact with model membranes. Yet, all peptides are very effective at destabilizing membranes.I hypothesise that peptides may affect membrane stability by disrupting the ordered water layer above the membrane. This project is part of a larger program to detail the initial stages of membrane destabilization by investigating intermolecular interactions responsible for structural modifications of membranes.