Dynamics of self-assembling ultrashort peptides into nanofibres: Hierarchical mechanism and role of on-pathway water dynamics

Dynamics of assembly processes is a poorly understood area of the broad field of spontaneous molecular self-assembly. In this paper, we present an all-atom Molecular Dynamics simulation study on the mechanism of spontaneous self-assembly of aqueous mixture of uncapped phenylalanine tripeptides into nanofibres. The mechanism was found to be hierarchical in nature and the spatial hierarchy of fusing molecular clusters was preserved in the final assembled state. Time-dependent analysis of intermolecular interactions revealed that the aggregation started with sidechain phenyl group contacts, mediated by the hydrophobic effect, eventually giving rise to a complex combination of interactions involving specific patterns of peptide-peptide hydrogen bonding. The final outcome of the assembly could not be explained solely on the basis of solute-solute interactions, suggesting an active role of the solvent. On-pathway slow dynamics of interfacial water molecules attached to the transient molecular clusters appeared to produce a significant disparity in the effective energy barrier for fusion between two alternative modes. This resulted in a possible kinetic control of preferential end-to-end association of anisotropic nanoclusters, leading to nanofibres as the dominant end-product of the assembly.