The mechanism of β-sheet formation remains
a fundamental issue in our understanding of the protein
folding process, but is hampered by the often encountered
kinetic competition between folding and aggregation. The
role of local versus nonlocal interactions has been probed
traditionally by mutagenesis of both turn and strand residues.
Recently, rigid organic molecules that impose a correct
chain reversal have been introduced in several small peptides
to isolate the importance of the long-range interactions.
Here, we present the incorporation of a well-studied β-turn
mimic, designated as the dibenzofuran-based (DBF) amino
acid, in the B1 domain of streptococcal protein G (B1G),
and compare our results with those obtained upon insertion
of the same mimic into the N-terminal β-hairpin of
B1G (O Melnyk et al., 1998, Lett Pept Sci 5:147–150).
The DBF-B1G domain conserves the structure and the functional
and thermodynamical properties of the native protein, whereas
the modified peptide does not adopt a native-like conformation.
The nature of the DBF flanking residues in the modified
B1G domain prevents the β-turn mimic from acting as
a strong β-sheet nucleator, which reinforces the idea
that the native β-hairpin formation is not driven by
the β-turn formation, but by tertiary interactions.