The nucleation of monomeric parallel beta-sheet-like structures and their self-assembly in aqueous solution.
The aromatic diacid residue 4,6-dibenzofuranbispropionic acid (1) was designed to nucleate a parallel beta-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 beta-sheet formation is favored in simple amides composed of 1, this hydrogen bonding interaction does not appear to be sufficient to nucleate parallel beta-sheet formation in the absence of hydrophobic clustering between the dibenzofuran portion of 1 and the hydrophobic side chains of the flanking alpha-amino acids. The subsequence --hydrophobic residue-1-hydrophobic residue-- is required for folding in the context of a nucleated two-stranded parallel beta-sheet structure. In all cases where the peptidomimetics can fold into two diastereomeric parallel beta-sheet structures having different hydrogen bonding networks, these conformations appear to exchange rapidly. The majority of the parallel beta-sheet structures evaluated herein undergo linked intramolecular folding and self-assembly, affording a fibrillar beta-sheet quaternary structure. To unlink folding and assembly, asymmetric parallel beta-sheet structures incorporating N-methylated alpha-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 beta-sheet-like structure in aqueous solution, as ascertained by a variety of spectroscopic and biophysical methods, increasing our understanding of parallel beta-sheet structure.
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Department of Chemistry and The Skaggs Institute of Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Fiori
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Lashuel
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Diaz
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Kelly
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D001572:Benzofurans / Q000737:chemistry*; D002942:Circular Dichroism; D005663:Furans / Q000737:chemistry*; D006860:Hydrogen Bonding; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D010455:Peptides / Q000737:chemistry; D011422:Propionates / Q000737:chemistry*; D017433:Protein Structure, Secondary; D017550:Spectroscopy, Fourier Transform Infrared; D014461:Ultracentrifugation
C119039:4,6-dibenzofuranbispropionic acid; D001572:Benzofurans; D005663:Furans; D010455:Peptides; D011422:Propionates