Published on Web 10/29/2003
A Reverse Turn Structure Induced by a D,L-r-Aminoxy Acid
Dimer
Dan Yang,*,† Jin Qu,† Wei Li,† De-Ping Wang,‡ Yi Ren,‡ and Yun-Dong Wu*,‡
Contribution from the Department of Chemistry, The UniVersity of Hong Kong, Pokfulam Road,
Hong Kong, and Department of Chemistry, The Hong Kong UniVersity of Science and
Technology, Clear Water Bay, Kowloon, Hong Kong, P. R. China
Received November 28, 2002; E-mail: yangdan@hku.hk; chydwu@ust.hk
Abstract: Our previous work revealed that two adjacent D-R-aminoxy acids could form two homochiral
N-O turns, with the backbone folding into an extended helical structure (1.88-helix). Here, we report the
conformational studies of linear peptides 3-6, which contain a D,L-R-aminoxy acid dimer segment. The
NMR and X-ray analysis of 3 showed that it folded into a loop conformation with two heterochiral N-O
turns. This loop segment can be used to constrain tetrapeptides 4 and 6 to form a reverse turn structure.
1H NMR dilution studies, DMSO-d6 addition studies, and 2D-NOESY data indicated that tetrapeptides 4
and 6 folded into reverse turn conformations featured by a head-to-tail 16-membered-ring intramolecular
hydrogen bond. In contrast, tetrapeptide 5 with L-Ala instead of Gly or D-Ala as the N-terminal amino acid
could not form the desired reverse turn structure for steric reasons. Quantum mechanics calculations showed
that model pentamide 7, with the same substitution pattern of 4, adopted a novel reverse turn conformation
featuring two heterochiral N-O turns (each of an 8-membered ring hydrogen bond), a cross-strand 16-
membered ring hydrogen bond, and a 7-membered ring γ-turn.
Introduction
designed by Smith and Hirschman was also shown to adopt a
reverse turn conformation.6 Here, we report that a D,L-R-
Reverse turns, in which the peptide chain reverses its
direction, are commonly observed secondary structures of
proteins and peptides and play important roles in protein folding
and receptor binding.1 The most common type is the â-turn,
defined by four residues at positions designated i to i + 3.
Significant efforts have been made to search for mimics of
various types of â-turns to modulate protein-protein and
protein-peptide interactions.2 Most of those â-turn mimics
contain fused rings or macrocyclic structures to constrain
conformations.3 Recently, significant progress has been made
in building reverse turns and hairpins using linear oligomers of
unnatural units.4-7 Seebach and co-workers reported an oligomer
of acyclic â-amino acids adopted hairpin conformations in
methanol.4a A reverse turn structure was observed by Gellman
and co-workers in peptides containing a (R,S)-dinipecotic acid
segment,4c-f which could promote the formation of hairpins in
the adjacent residues. In addition, the configurations of the
central two â-amino acids were critical to the stability of the
reverse turn and hairpin structures. A D,L,D,L-tetrapyrrolinone
aminoxy acid dimer segment can induce a novel reverse turn
structure in the peptide backbone.
(3) For recent examples of ring-fused or macrocyclic reverse turn mimics,
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Med. Chem. 2002, 45, 1395. (b) Jiang, L.; Burgess, K. J. Am. Chem. Soc.
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† The University of Hong Kong.
‡ The Hong Kong University of Science and Technology.
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J. AM. CHEM. SOC. 2003, 125, 14452-14457
10.1021/ja029514j CCC: $25.00 © 2003 American Chemical Society