Cross-β structures are crucial in driving protein folding and aggregation. However, due to their strong aggregating tendency, the precise control of the self-assembly of β-sheet-forming peptides remains a challenge. We propose a molecular geometry strategy to study and control the self-assembly of cross-β structures. We conjugate the peptide with shape-persistent polyhedral oligomeric silsesquioxane (POSS), which acts as a hydrophilic head and senses the solvent environment. The POSS-peptide amphiphiles display two distinct self-assembly pathways: twisted nanoribbons transforming into either nanotubes at low water content or flat nanoribbons at high water content. The peptide packing in flat nanoribbons is predominantly modulated by POSS, diverting the system away from crystal formation, which is the absolute lowest energy state of pure peptide self-assemblies. For the first time, we have demonstrated that POSS can serve as a useful tool to adjust the interactions between cross-β strands, achieving fine-tuning of the pathway complexity (i.e., the kinetic and thermodynamic aspects of peptide self-assembly). With this versatile molecular platform incorporating multiple functionalities of POSS and programable peptide sequences, this study provides a platform to exploit cross-β-based nanomaterials with functional and pathological significance.
Keywords: Cross-β structures; Free energy landscape; Morphology transition dynamics; POSS-peptide amphiphiles; Pathway complexity.
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