Nucleated Antiparallel β-Sheet That Folds and Undergoes Self-Assembly:  A Template Promoted Folding Strategy toward Controlled Molecular Architectures

The aromatic amino acid residue 4-(2-aminoethyl)-6-dibenzofuranpropanoic acid ( 1 ) nucleates antiparallel β-sheet folding in tridecapeptides which subsequently self-assemble into fibrils. Residue 1 functions as a folding nucleator by facilitating intramolecular hydrogen bonding between the flanking α-amino acid residues and by favoring the formation of a hydrophobic cluster composed of the dibenzofuran skeleton and the hydrophobic side chains of the flanking α-amino acids. The hydrogen bonded hydrophobic cluster (i.e., −hydrophobic α-amino acid residue− 1 −hydrophobic α-amino acid residue−) nucleates β-sheet folding in relatively small peptides that have a propensity to fold. The α-amino acid sequence design determines the self-association pathway and the resulting molecular architecture. The approach described here takes advantage of template driven hydrophobic clusters and template derived conformational biases to nucleate folding in small peptides, affording β-sheets which subsequently self-associate into well-defined quaternary structures. This strategy allows significant α-amino acid sequence variations to be accommodated in the resulting β-sheet-based macromolecular assembly without interfering with the folding pathway.