"Mirror image" reverse turns promote .beta.-hairpin formation

Haque, Tasir S.; Little, Jennifer C.; Gellman, Samuel H.

doi:10.1021/ja00088a067

Cited by 123 publications

(81 citation statements)

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“…The ability of a centrally positioned D-Pro-Xxx segment to stabilize -hairpin conformations in short synthetic peptides is well established by NMR studies in solution [1][2][3][4][5][6][7][8] and X-ray diffraction studies in crystals. [9][10][11][12][13][14] Robust synthetic hairpin scaffolds provide an opportunity to examine the effect of turn stereochemistry on the orientation of the antiparallel strands 14 and to probe cross-strand interactions between side chains placed at facing positions.…”

Section: Introductionmentioning

confidence: 99%

Peptide hairpins with strand segments containing α‐ and β‐amino acid residues: Cross‐strand aromatic interactions of facing Phe residues

et al. 2005

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The incporation of beta-amino acid residues into the strand segments of designed beta-hairpin leads to the formation of polar sheets, since in the case of beta-peptide strands, all adjacent carbonyl groups point in one direction and the amide groups orient in the opposite direction. The conformational analysis of two designed peptide hairpins composed of alpha/beta-hybrid segments are described: Boc-Leu-betaPhe-Val-(D)-Pro-Gly-Leu-betaPhe-Val-OMe (1) and Boc-betaLeu-Phe-betaVal-D-Pro-Gly-betaLeu-Phe-betaVal-OMe (2). A 500-MHz 1H-NMR (nuclear magnetic resonance) analysis in methanol supports a significant population of hairpin conformations in both peptides. Diagnostic nuclear Overhauser effects (NOEs) are observed in both cases. X-ray diffraction studies on single crystals of peptide 1 reveal a beta-hairpin conformation in both the molecules, which constitute the crystallographic asymmetric unit. Three cross-strand hydrogen bonds and a nucleating type II' beta-turn at the D-Pro-Gly segment are observed in the two independent molecules. In peptide 1, the betaPhe residues at positions 2 and 7 occur at the nonhydrogen-bonding position, with the benzyl side chains pointing on opposite faces of the beta-sheet. The observed aromatic centroid-to-centroid distances are 8.92 A (molecule A) and 8.94 A (molecule B). In peptide 2, the aromatic rings must occupy facing positions in antiparallel strands, in the NMR-derived structure. Peptide 1 yields a normal "hairpin-like" CD spectrum in methanol with a minimum at 224 nm. The CD spectrum of peptide 2 reveals a negative band at 234 nm and a positive band at 221 nm, suggestive of an exciton split doublet. Modeling of the facing Phe side chains at the hydrogen-bonding position of a canonical beta-hairpin suggests that interring separation is approximately 4.78 A for the gauche+ gauche- (g+ g-) rotamer. A previously reported peptide beta-hairpin composed of only alpha-amino acids, Boc-Leu-Phe-Val-D-Pro-Gly-Leu-Phe-Val-OMe also exhibited an anomalous far-UV (ultraviolet) CD (circular dichroism) spectrum, which was interpreted in terms of interactions between facing aromatic chromophores, Phe 2 and Phe 7 (C. Zhao, P. L. Polavarapu, C. Das, and P. Balaram, Journal of the American Chemical Society, 2000, Vol 122, pp. 8228-8231).

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Section: Introductionmentioning

confidence: 99%

Peptide hairpins with strand segments containing α‐ and β‐amino acid residues: Cross‐strand aromatic interactions of facing Phe residues

et al. 2005

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“…A short two-residue loop segment ( D PG) was used to link the two-strand antiparallel ␤-sheet. D PG stabilizes the type II= ␤-turn and promotes the formation of ␤-hairpin conformations (13,30). The ␤-hairpin was further stabilized by a disulfide bridge.…”

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confidence: 99%

Strand Length-Dependent Antimicrobial Activity and Membrane-Active Mechanism of Arginine- and Valine-Rich β-Hairpin-Like Antimicrobial Peptides

Dong

Shan

et al. 2012

Antimicrob Agents Chemother

123

107

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bAntimicrobial peptides with amphipathic ␤-hairpin-like structures have potent antimicrobial properties and low cytotoxicity. The effect of VR or RV motifs on ␤-hairpin-like antimicrobial peptides has not been investigated. In this study, a series of ␤-hairpin-like peptides, Ac-C(VR) n D PG (RV) n C-NH 2 (n ‫؍‬ 1, 2, 3, 4, or 5), were synthesized, and the effect of chain length on antimicrobial activity was evaluated. The antimicrobial activity of the peptides initially increased and then decreased with chain length. Longer peptides stimulated the toxicity to mammalian cells. VR3, a 16-mer peptide with seven amino acids in the strand, displayed the highest therapeutic index and represents the optimal chain length. VR3 reduced bacterial counts in the mouse peritoneum and increased the survival rate of mice at 7 days after Salmonella enterica serovar Typhimurium infection in vivo. The circular dichroism (CD) spectra demonstrated that the secondary structure of the peptides was a ␤-hairpin or ␤-sheet in the presence of an aqueous and membrane-mimicking environment. VR3 had the same degree of penetration into the outer and inner membranes as melittin. Experiments simulating the membrane environment showed that Trp-containing VRW3 (a VR3 analog) tends to interact preferentially with negatively charged vesicles in comparison to zwitterionic vesicles, which supports the biological activity data. Additionally, VR3 resulted in greater membrane damage than melittin as determined using a flow cytometry-based membrane integrity assay. Collectively, the data for synthetic lipid vesicles and whole bacteria demonstrated that the VR3 peptide killed bacteria via targeting the cell membrane. This assay could be an effective pathway to screen novel candidates for antibiotic development.

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“…Circular dichroism and 2D NMR experiments established that there are close contacts between residues in the helix and hairpin segments, that there are interhelical interactions, and that each monomer is in a symmetrical environment. Key features include the hinge region and the constrained ␤-hairpin motif, established by a ␤-turn-forming DPro-Ser sequence (24,25). While solution-state biophysical experiments clearly revealed the presence of a defined oligomeric state, the exact nature of the structure and the forces contributing to the observed native-protein-like stability remained unknown.…”

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confidence: 99%

X-ray structure analysis of a designed oligomeric miniprotein reveals a discrete quaternary architecture

Ali

Peisach

Allen

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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The x-ray crystal structure of an oligomeric miniprotein has been determined to a 1.2-Å resolution by means of multiwavelength anomalous diffraction phasing with selenomethionine analogs that retain the biophysical characteristics of the native peptide. Peptide 1, comprising ␣ and ␤ secondary structure elements with only 21 aa per monomer, associates as a discrete tetramer. The peptide adopts a previously uncharacterized quaternary structure in which ␣ and ␤ components interact to form a tightly packed and well defined hydrophobic core. The structure provides insight into the origins of the unusual thermal stability of the oligomer. The miniprotein shares many characteristics of larger proteins, including cooperative folding, lack of 1-anilino-8-naphthalene sulfonate binding, and limited deuterium exchange, and possesses a buried surface area typical of native proteins. O ligomerization is a fundamental strategy for generating protein structural and functional complexity in nature. Many large proteins are believed to have arisen from oligomeric precursors that, by means of gene duplication and fusion, have become one encoded protein (1). Some examples are the ribosome anti-association factor eIF6 (2), the periplasmic binding proteins (3, 4), and the eightfold ␤͞␣ barrel (5). Functionally, many proteins (6) are inactive in the monomeric state but are active as a dimer or higher-order oligomer; examples include GCN4 (7) and MCP-1 (8).We are interested in studying the structural and functional advantages conferred by protein oligomerization. We thus set out to create miniproteins that would adopt a defined oligomeric state. Miniprotein models have been used to investigate biological processes and to model larger proteins through the incorporation of catalytic or other functionality (9-11). Oligomeric miniproteins serve as minimal model systems for quaternary structure formation. Moreover, they constitute platforms for probing whether more complex oligomeric structures might ultimately support function.The strategy for oligomerization was inspired by ''domain swapping,'' or the exchange of association partners, an important evolutionary mechanism for protein oligomerization (12)(13)(14)(15). This strategy has previously been used for the design of a coiled-coil domain-swapped dimer (16). The prototypic ␤␤␣ (BBA) motif BBA5 (Fig. 1) was chosen as the building block because it represents a discretely folded and structured miniprotein motif (17,18). This motif includes interactions between secondary structural elements, thus presenting an opportunity to favor similar interactions between monomers within an oligomer. Because it has been reported that shortening the linker between domains favors domain-swapped oligomers (19, 20), we introduced a bias toward oligomerization in the BBA motif by varying the length of the 3-aa hinge region between secondary structural elements (21). Our approach for the discovery of homooligomers of peptides with ␤␤␣ supersecondary structure was based on a complementary design and screening ...

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"Mirror image" reverse turns promote .beta.-hairpin formation

Cited by 123 publications

References 0 publications

Peptide hairpins with strand segments containing α‐ and β‐amino acid residues: Cross‐strand aromatic interactions of facing Phe residues

Peptide hairpins with strand segments containing α‐ and β‐amino acid residues: Cross‐strand aromatic interactions of facing Phe residues

Strand Length-Dependent Antimicrobial Activity and Membrane-Active Mechanism of Arginine- and Valine-Rich β-Hairpin-Like Antimicrobial Peptides

X-ray structure analysis of a designed oligomeric miniprotein reveals a discrete quaternary architecture

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