Probing the Self-Assembly Mechanism of Diphenylalanine-Based Peptide Nanovesicles and Nanotubes

Nanostructures, particularly those from peptide self-assemblies, have attracted great attention lately due to their potential applications in nanotemplating and nanotechnology. Recent experimental studies reported that diphenylalanine-based peptides can self-assemble into highly ordered nanostructures such as nanovesicles and nanotubes. However, the molecular mechanism of the self-organization of such well-defined nanoarchitectures remains elusive. In this study, we investigate the assembly pathway of 600 diphenylalanine (FF) peptides at different peptide concentrations by performing extensive coarse-grained molecular dynamics (MD) simulations. Based on forty 0.6–1.8 μs trajectories at 310 K starting from random configurations, we find that FF dipeptides not only spontaneously assemble into spherical vesicles and nanotubes, consistent with previous experiments, but also form new ordered nanoarchitectures, namely, planar bilayers and a rich variety of other shapes of vesicle-like structures including toroid, ellipsoid, discoid, and pot-shaped vesicles. The assembly pathways are concentration-dependent. At low peptide concentrations, the self-assembly involves the fusion of small vesicles and bilayers, whereas at high concentrations, it occurs through the formation of a bilayer first, followed by the bending and closure of the bilayer. Energetic analysis suggests that the formation of different nanostructures is a result of the delicate balance between peptide–peptide and peptide–water interactions. Our all-atom MD simulation shows that FF nanostructures are stabilized by a combination of T-shaped aromatic stacking, interpeptide head-to-tail hydrogen-bonding, and peptide–water hydrogen-bonding interactions. This study provides, for the first time to our knowledge, the self-assembly mechanism and the molecular organization of FF dipeptide nanostructures.