The nucleation of monomeric parallel β-sheet-like structures and their self-assembly in aqueous solution

Abstract

The aromatic diacid residue 4,6-dibenzofuranbispropionic acid (1) was designed to nucleate a parallel β-sheet-like structure in small peptides in aqueous solution via a hydrogen-bonded hydrophobic cluster. Even though a 14-membered ring hydrogen bond necessary for parallel β-sheet formation is favored in simple amides composed of 1, this hydrogen bonding interaction does not appear to be sufficient to nucleate parallel β-sheet formation in the absence of hydrophobic clustering between the dibenzofuran portion of 1 and the hydrophobic side chains of the flanking α-amino acids. The subsequence -hydrophobic residue-1-hydrophobic residue- is required for folding in the context of a nucleated two-stranded parallel β-sheet structure. In all cases where the peptidomimetics can fold into two diastereomeric parallel β-sheet structures having different hydrogen bonding networks, these conformations appear to exchange rapidly. The majority of the parallel β-sheet structures evaluated herein undergo linked intramolecular folding and self-assembly, affording a fibrillar β-sheet quaternary structure. To unlink folding and assembly, asymmetric parallel β-sheet structures incorporating N-methylated α-amino acid residues have been synthesized using a new solid phase approach. Residue 1 facilitates the folding of several peptides described within affording a monomeric parallel β-sheet-like structure in aqueous solution, as ascertained by a variety of spectroscopic and biophysical methods, increasing our understanding of parallel β-sheet structure.