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Turn Segment for Hairpin Formation

Two types of b-dipeptide turn segments have been used to connect antiparallel b-peptide strands and nucleate b-peptide hairpin conformations.

The first one imagined by Gellman and his group is a 12-membered H-bonded turn generated by a heterochiral dinipecotic acid (Nip, the b2-homolog of proline: b 2-HPro) sequence [162, 163]. X-ray crystal structure of a designed b-tetrapeptide (23, Fig. 2.14A) show the expected antiparallel hairpin conformation, all strand residues displaying antiperiplanar arrangement around the C(a)-C(b) bond [162]. The second approach developed by Seebach and co-workers (24, Fig. 2.14B) exploits the propensity of mixed b2/b3-dipeptides to populate 10-membered H-bonded turn (see Section 2.4.2.1 and Fig. 2.10) [159, 164]. Detailed NMR spectroscopy and MD simulation analysis of b-hexapeptide 24 in CD3OH revealed significant (an estimation of 20-30% was given by MD) hairpin population. There was however no evidence for secondary structure in water. The structural similarity between the 10-membered turn segment in 24 and a type II' a-peptide b-turn is illustrated in Fig. 2.14E. Interestingly, the formation of b-peptide 10-membered H-bonded turns was also found to be strongly promoted by b2'2-geminally substituted amino acids units such as achiral 1-aminomethylcyclohexanecarboxylic acid [51]. The hairpin structures in both 23 and 24 are characterized by the unidirec-tionality of the C=O and NH bonds within each strand segment. However, as a consequence of their different turn geometry: a 12-membered turn closed by H-bonds between C=Oi and NHi+3, and a 10-membered turn closed by H-bonds between NHi and C=Oi+1, antiparallel hairpins formed by b-peptides 23 and 24 display opposite sheet polarities. Backbone torsion angle values (X-ray and NMR) for selected b-amino acids residues within extended strand segments of 23 and 24 are close to ideal values for b-peptide pleated sheets: f = —120° (or 120°), y1 = 180°, c = 120° (or —120°).

Optimal pre-organization of the /-peptide backbone towards the formation of open-chain turn-like motifs was found to be promoted by unlike-y2' 4-amino acid residues [165-166]. This design principle can be rationalized by examination of the two conformers free of syn-pentane interaction (I and II, Fig. 2.14C). y2;4-peptides built from either homochiral or heterochiral unlike-y2'4-amino acid units adopt reverse turn-like structure stabilized by 14-membered H bond (e.g. 25, Fig. 2.14D). y-Peptide turn conformations compare well with the type II' b-hairpin

Fig. 2.14 Nonperiodic structures formed by b- and g-peptides. b-peptide antiparallel hairpin structures with (A) a 12-membered R/S dinipecotic turn segment (e.g. 23, X-ray structure) [162] and (B) with the 10-membered turn formed by mixed b2/b3" dipeptide sequence (e.g. 24, structure derived from NMR data in CD3OH) [164]. (C) The two conformation free of destabilizing syn-pentane interaction in g2,4-amino acid with unlike configuration. (D) 14-membered H-

Fig. 2.14 Nonperiodic structures formed by b- and g-peptides. b-peptide antiparallel hairpin structures with (A) a 12-membered R/S dinipecotic turn segment (e.g. 23, X-ray structure) [162] and (B) with the 10-membered turn formed by mixed b2/b3" dipeptide sequence (e.g. 24, structure derived from NMR data in CD3OH) [164]. (C) The two conformation free of destabilizing syn-pentane interaction in g2,4-amino acid with unlike configuration. (D) 14-membered H-

bonded turn induced by g-peptides consisting of unlike-g2'4-amino acid residues (hetero-chiral sequence) (e.g. 25, X-ray structure) [166]. (E) Comparison of the turn segment found in b- and g-peptide 24 and 25 with a naturally occuring type II' b-turn of «-polypeptides together with backbone dihedral angles in (°). Torsion angles with comparable values are shown in bold [164, 166].

motif of naturally occurring a-peptides, thus suggesting that short-chain g-peptides with the right substitution pattern could be used as b-turn mimetics in drug design.

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