Initial Aggregation and Ordering Mechanism of Diphenylalanine from Microsecond All-Atom Molecular Dynamics Simulations.

Self-assembled diphenylalanine (FF) nanostructures have recently been demonstrated to be interesting materials for antibacterial and anticancer applications. These applications, among others, seek to take advantage of the high-order and resulting appealing physical properties of FF nanostructures by modifying the peptide in some way to achieve specific functionality. To rationally design modifications to the dipeptide that allow for this behavior, the driving forces of FF self-assembly must be understood. Molecular simulations have been utilized to assess these properties but have yielded conflicting conclusions due to inconsistencies in models chosen as well as the lack of quantitative analyses on the specific driving forces. Here, we present an all-atom explicit solvent molecular dynamics-based study on different length scales of FF aggregation. We utilize a free energy decomposition analysis as well as a dimer cluster analysis to identify the initial aggregation driving force to be FF intermolecular electrostatics, whereas solvent-mediated forces drive crystal growth. These data are consistent with the hypothesis that all hydrophobic dipeptides will have a similar initial aggregation mechanism until a critical aggregate size is reached, at which point crystallization occurs and subsequent crystal growth is dominated by solvent-mediated forces. We demonstrate that this proposed mechanism is testable by infrared spectroscopy focusing on the blueshift of the amide I peak as well as the ordering of the carboxylate peak.