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Despite their pivotal role in protein function and
antibody binding affinity, β-hairpins
bearing long non-canonical loops are a challenge to modern synthesis because of
the large entropic penalty associated with their folding. Little is known about
the contribution and impact of stabilizing motifs on the folding of β-hairpins of variable length and plasticity. Here we report a direct comparison between these b-straps thermodynamics and their thermal stability
behavior using several local spectroscopic probes of the folding/unfolding
landscape. The judicious cooperative interactions crafted in β-Strap RW(VW)•••(WV/H)WE (strap = strand + cap) greatly stabilized hairpins with up to 10-residue loops lacking an innate nucleating-turn
locus (Tmup to 52 oC;
88 ± 1% folded at 291 K). The present design of
novel β-straps aims to
provide the foundation to study new classes of long hairpins and ultimately offer
an attractive alternative to macrocyclic peptides for the mimicry of functional
loops from proteins and antibodies.