Impact of amylenes in dipeptide-mediated phospholipid vesicle integrity and aggregation

Interactions between lipid membranes are central to biological, biochemical, and biophysical processes. While adhesion between intact vesicles typically requires complex molecular linkers to overcome electrostatic and hydration repulsions, aggregation involves bilayer disruption and loss of vesicle integrity, a phenomenon more often associated with pathology. Here we report a minimal and straightforward route to induce aggregation of zwitterionic vesicles through the combined action of diphenylalanine (Phe-Phe), a dipeptide motif of the Alzheimer's β-amyloid peptide, and amylene, a small apolar alkene used as a chloroform stabilizer. Using NMR spectroscopy, microscopy, and thermodynamic and nanomechanical characterization, we demonstrate that Phe-Phe alone perturbs bilayer organization only mildly, but in the presence of amylene it synergistically drives membrane disruption and vesicle aggregation. These results highlight how the interplay of small molecules can reorganize zwitterionic membranes and eventually induce spontaneous aggregation. Impact of amylenes in dipeptide-mediated phospholipid vesicle integrity and aggregation. Phospholipids are commonly used as in vitro models for cellular membranes. When combined with diphenylalanine and amylenes, they promote aggregation of vesicles, modifying their strength and thermodynamic properties. A phenyl-amylene-phenyl bridge appears to be the key factor responsible for this effect. • Diphenylalanine peptide induces greater membrane disorder in the presence of amylenes. • The synergistic peptide-alkene action leads to weaker lipid bilayer nanomechanics. • Large peptide and amylene concentration destabilizes the bilayer and can form pores. • Vesicle aggregation facilitated by peptide-alkene complexes via a phenyl-amylene-phenyl. • bridge.