Stoichiometry-Controlled Structural Transformation of Diphenylalanine Nanoassemblies through Coassembly with Charged Dipeptides

Peptide self-assembly produces a wide range of well-structured nanostructures, offering significant potential for biomedical and nanotechnological applications. However, controlling the morphologies of these assemblies is considerably challenging due to their intricate polymorphisms and complex responsiveness to environmental changes. In this study, we present a stoichiometry-controlled strategy to finely tune the morphology of supramolecular nanostructures by coassembling diphenylalanine (FF) with charged aromatic dipeptides. Diverse nanostructures including one-dimensional nanotubes, two-dimensional planar sheets, and three-dimensional nanovesicles are obtained by varying the ratio of two peptide building blocks. These structures are predicted by coarse-grained simulations, subsequently validated for stability by all-atom simulations, and further confirmed by experiments. Notably, planar sheets, rarely seen in FF self-assembly, emerge frequently when coassembling FF with high ratios of charged dipeptides. Interaction analysis reveals that the formation of these diverse nanostructures is driven by aromatic stacking and modulated by the strength of electrostatic repulsion. Remarkably, pH-responsive environments induce transformations between nanovesicles and planar sheets, underscoring their potential for biomedical applications. This study underscores the potential of a stoichiometry-controlled strategy to design multidimensional nanostructures with tunable morphologies, offering significant promise for nanomedicine applications, such as precision-targeted drug delivery systems.