![]() 13 Another example of cross-strand π−π contacts is the β-hairpin capping motif proposed by Andersen and co-workers, which consists of the N-terminal alkanoyl-Trp residue and the C-terminal triad Trp-Thr-Gly-NH 2: in this motif the two indole groups adopt a face-to-edge orientation, while the Thr side chain is involved in a H-bond with the alkanoyl group. For example, Starovasnik and co-workers developed the so called Trp zipper, in which two Trp−Trp cross-strand pairs contribute to the stabilization of a short hairpin induced by a type I′ (Asn-Gly) or II′ (Gly-Asn or d-Pro- l-Asn) β-turn. 12īesides cyclopeptides, linear peptides have also been proposed to mimic β-hairpins: in this case, strong non-covalent interactions between the two β-strands in combination with a β-turn motif have been exploited to compensate the lack of a macrocyclic structure. 9 For example, Meldal, Schoffelen, and co-workers 10 developed small antibody mimetics (β-bodies) consisting of a cyclopeptide containing the following structural elements: the β-turn motif Pro-Gly, the two arms with alternating Thr residues to favor an extended conformation, 11 and side-chain-to-side-chain cyclization of the N-terminal and C-terminal residues by a triazole crosslinker. 6e Other strategies for the design of β-hairpins take advantage of natural or chemically modified amino acids with β-branched side chains that favor the formation of β-strands. 6g This cyclic template has been used not only to assemble protein domains, like four-helix bundles and β-barrels, 6g but also to generate chemical diversity in combinatorial libraries. 6j, 8 In the late eighties, Mutter and co-workers designed a backbone-cyclized decapeptide containing two Pro-Gly β-turns that connect two three-residue-long arms. 7 This cyclic scaffold is particularly useful for the mimicry of short protein loops, and also for the development of synthetic antibiotics and vaccines. 6 About two decades ago, Robinson and co-workers introduced a β-hairpin scaffold consisting of a backbone-cyclized peptide with d-Pro- l-Pro as type II′ β-turn-inducer. 1, 5 Moreover, a variety of chemical modifications have been used to achieve well-defined β-hairpin structures aiming at the mimicry of native β-hairpins as well as at the development of peptide scaffolds and templates. 2 Since β-hairpins are involved not only in the folding of globular proteins 1, 3 but also in protein-protein interactions, 4 they have been intensively investigated. 1 A typical example of β-hairpin is found in the C2H2 zinc-finger, a DNA-binding domain in which a β-hairpin and a short helix are kept together by coordinating a zinc ion with two Cys thiols from the β-hairpin and two His imidazole rings from the helix. Both the NMR and MD data confirm that our acyclic β-hairpin scaffold is highly versatile as regards the amino-acid composition of the β-sheet face opposite to the cationic−aromatic one.Ī β-hairpin is a protein supersecondary structure that consists of two antiparallel β-strands connected by a β-turn or a short loop. To demonstrate the robustness of the scaffold, we elucidated the NMR structures and performed molecular dynamics (MD) simulations of a series of peptides displaying mainly non-β-branched, poorly β-sheet-prone residues at the X positions. The high conformational stability of the scaffold results from tight contacts between cross-strand cationic and aromatic side chains, combined with the strong tendency of the d-Pro- l-Pro dipeptide to induce a type II′ β-turn. Since linear peptides are synthetically more easily accessible than cyclic ones, but are structurally less well-defined, we propose XWXWXpPXK(/R)X(R) as an acyclic but still rigid β-hairpin scaffold that is robust enough to accommodate different types of side chains, regardless of the secondary-structure propensity of the X residues. The β-hairpin is a structural element of native proteins, but it is also a useful artificial scaffold for finding lead compounds to convert into peptidomimetics or non-peptide structures for drug discovery.
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