The effect of homologated phenylalanine side chains on the conformation and assembly of peptide helices was investigated on five pentapeptides. Intramolecular aromatic interactions were not present in the parent peptide but were present in the peptides containing the higher homologs of Phe. hPhe and h2Phe residues may have aromatic interactions that could induce preferential folding and aggregation of peptides containing them.
ABSTRACT
Interactions between aromatic side chains of amino acids stabilize the fold and assembly of short peptides. The aromatic π…π and C-H…π interactions have been widely explored in the design of short peptides with specific folding and aggregation patterns. In the present study, we investigated the effect of homologated phenylalanine side chains on the conformation and assembly of peptide helices through X-ray crystallographic structure determination and analysis of five pentapeptides. The parent peptide Boc-Phe-Aib-Aib-Leu-Phe-NHiPr (1) and its four variations were synthesized, in which either one or both of the Phe side chains have been modified by inserting one (homophenylalanine, hPhe; -CH2-CH2-C6H5) or two (h2Phe; -CH2-CH2-CH2-C6H5) additional CH2 groups in the side chain, and their crystal structures were analyzed. The results show that intramolecular aromatic interactions are not present in the parent peptide but are present in the peptides containing the higher homologs of Phe. In peptides that did not show intramolecular aromatic interactions, the effect of increased length of the side chain of Phe residues manifested as intermolecular interactions leading to ordered packing in crystals. The results indicate the potential of hPhe and h2Phe residues to have aromatic interactions that could induce preferential folding and aggregation of peptides containing them.
