Membrane Determinants Affect Fibrillation Processes of β-Sheet Charged Peptides

Assembly of fibrillar peptide structures is dependent both upon their intrinsic propensities toward β-structure formation, as well as on structural modulation by external molecular factors. β-sheet structures may either be designed to form useful assemblies or be the undesired consequence of protein denaturation to toxic amyloid structures in several neurodegenerative diseases. Membrane bilayers have been implicated as primary initiators and modulators of amyloid fibrillation and the reasons for this effect are yet to be elucidated. Here, we employed a set of three charged peptides having the tendency to form β-sheet fibrils, to investigate the effect of zwitterionic and negatively charged bilayer vesicles on their assembly structures. Microscopic and spectroscopic experiments revealed intimate relationship between peptide/membrane charges and fibrillation properties. Electrostatic attraction was apparent between oppositely charged peptides and vesicles; however, such interactions did not appear to significantly modulate fibril morphologies of either the net anionic peptide or the cationic one. Yet, a dramatic structural effect was observed when the nominal zwitterionic peptide underwent fibrillation in the presence of negatively charged vesicles. Assemblies of this peptide display a net positive charge, which facilitated the counterionic interactions with the vesicles. Furthermore, these interactions templated a unique twisted fiber morphology demonstrating the dramatic effect membrane-mediated interactions exert on fibril morphologies.