Stereochemical Requirements for β-Hairpin Formation:  Model Studies with Four-Residue Peptides and Depsipeptides

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

doi:10.1021/ja960429j

Cited by 266 publications

(222 citation statements)

References 45 publications

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“…2) that we have previously shown to adopt a ␤-hairpin conformation in aqueous solution (14,16). D P contains a central D-Pro-Gly segment to induce formation of a ''mirror image'' ␤-turn (type IЈ or IIЈ) (32)(33)(34)(35)(36); the local right-handed twist of such turns is compatible with the right-handed twist of the strands in a ␤-sheet (37). Although D-proline is not a proteinogenic residue, structural analysis of 12-mer D P via two-dimensional NMR shows that this peptide adopts a native-like two-stranded antiparallel ␤-sheet conformation in aqueous solution (14,16).…”

Section: Resultsmentioning

confidence: 99%

“…Replacing D-Pro with L-Pro completely abolishes ␤-hairpin formation (14,16,18,34,36), and the L-Pro diastereomer of D P provides an excellent representation of the completely unfolded state of D P (i.e., an excellent source of ␦ U values). Closing off the open end of D P with a second D-Pro-Gly segment generates a cyclic peptide, c( D P) 2 , which has a very high ␤-sheet population (i.e., an excellent source of ␦ F values) (16).…”

Section: Resultsmentioning

confidence: 99%

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Length-dependent stability and strand length limits in antiparallel β-sheet secondary structure

Stanger

Syud

Espinosa

et al. 2001

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

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144

187

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Designed peptides that fold autonomously to specific conformations in aqueous solution are useful for elucidating protein secondary structural preferences. For example, autonomously folding model systems have been essential for establishing the relationship between ␣-helix length and ␣-helix stability, which would be impossible to probe with ␣-helices embedded in folded proteins. Here, we use designed peptides to examine the effect of strand length on antiparallel ␤-sheet stability. ␣-Helices become more stable as they grow longer. Our data show that a two-stranded ␤-sheet (''␤-hairpin'') becomes more stable when the strands are lengthened from five to seven residues, but that further strand lengthening to nine residues does not lead to further ␤-hairpin stabilization for several extension sequences examined. (In one case, all-threonine extension, there may be an additional stabilization on strand lengthening from seven to nine residues.) These results suggest that there may be an intrinsic limit to strand length for most sequences in antiparallel ␤-sheet secondary structure.M ost proteins must fold to a specific three-dimensional shape to perform their biological functions. There is great interest in identifying the factors that determine native conformations; however, despite considerable study, it is not yet possible to predict tertiary folding patterns on the basis of primary structure. A few secondary structures (especially ␣-helix and ␤-sheet) recur throughout known protein structures, and understanding the forces that control conformational preferences within the common secondary structures should contribute to our understanding of conformational preferences at tertiary and quaternary levels. The ␣-helix has been very carefully scrutinized because there are well-established design principles for creating synthetic peptides that adopt ␣-helical secondary structure in the absence of a specific tertiary context (1-7). Until recently, the lack of autonomously folding ␤-sheet model systems made it impossible to conduct analogous studies with this secondary structure (8). In the past several years, however, a number of short peptides (9-24 residues) that display double-or triple-stranded antiparallel ␤-sheet conformations in aqueous solution have been reported (9-11). These model systems provide thermodynamic (12-23) and kinetic (24) insights on ␤-sheet folding behavior. [Solvent-exposed ␤-sheets in specific tertiary contexts have provided a complementary approach for elucidation of ␤-sheet conformational preferences (25,26)]. Here, we show how small designed peptides can be used to assess an aspect of ␤-sheet stability that has not previously been addressed experimentally.␣-Helices become more stable as the length of the helix increases (5-7). This length-dependent effect on conformational stability arises because helix initiation is thermodynamically unfavorable but helix propagation is favorable, at least for some residues (1, 2). Analogous length-dependent stabilization is observed for double-helical nuclei...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Length-dependent stability and strand length limits in antiparallel β-sheet secondary structure

Stanger

Syud

Espinosa

et al. 2001

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

Self Cite

144

187

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“…Thus, the type I + GI P-bulge turns are more prevalent than the type I in P-hairpins, suggesting that the former is more favorable for /?-hairpin formation, as we observe in our designed peptide models. Previous studies indicated that type I turns do not have the proper geometry toward the right-handed twist commonly observed in protein P-sheets (Sibanda & Thornton, 1985;Haque et al, 1994Haque et al, , 1996Haque & Gellman, 1997) and suggest why this type of turn may not be favorable for /?-hairpin formation. The results obtained with our peptide systems are consistent with this suggestion.…”

Section: Comparison Of P-hairpin 4:4 and P-hairpin 3:5 Formationmentioning

confidence: 99%

“…Some peptides containing non-natural amino acids (Haque et al, 1994(Haque et al, , 1996 as well as nonpeptide scaffolds able to bring the two strands together (LaBrenz & Kelly, 1995;Nesloney & Kelly, 1996;Nowick et al, 1996aNowick et al, , 1996b were designed with the purpose of studying P-hairpin formation. However, as far as we know, no stabilizing interstrand side-chain interactions were identified in these model systems.…”

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confidence: 99%

Cross‐strand side‐chain interactions versus turn conformation in β‐hairpins

1997

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A series of designed peptides has been analyzed by 'H-NMR spectroscopy in order to investigate the influence of cross-strand side-chain interactions in @hairpin formation. The peptides differ in the N-terminal residues of a previously designed linear decapeptide that folds in aqueous solution into two interconverting P-hairpin conformations, one with a type I turn (P-hairpin 4:4) and the other with a type I + G1 P-bulge turn (P-hairpin 3:5). Analysis of the conformational behavior of the peptides studied here demonstrates three favorable and two unfavorable cross-strand side-chain interactions for P-hairpin formation. These results are in agreement with statistical data on side-chain interactions in protein P-sheets. All the peptides in this study form significant populations of the P-hairpin 3:5, but only some of them also adopt the @-hairpin 4:4. The formation of @-hairpin 4:4 requires the presence of at least two favorable cross-strand interactions, whereas P-hairpin 3:5 seems to be less susceptible to side-chain interactions. A protein database analysis of &hairpins 3:5 and P-hairpins 4:4 indicates that the former occur more frequently than the latter. In both peptides and proteins, P-hairpins 3:5 have a larger right-handed twist than P-hairpins 4:4, so that a factor contributing to the higher stability of @-hairpin 3:5 relative to P-hairpin 4:4 is due to an appropriate backbone conformation of the type I + GI P-bulge turn toward the right-handed twist usually observed in protein P-sheets. In contrast, as suggested previously, backbone geometry of the type I turn is not adequate for the right-handed twist. Because analysis of buried hydrophobic surface areas on protein P-hairpins reveals that P-hairpins 3:5 bury more hydrophobic surface area than P-hairpins 4:4, we suggest that the right-handed twist observed in P-hairpin 3:5 allows a better packing of side chains and that this may also contribute to its higher intrinsic stability.Keywords: P-hairpin conformation; P-sheet twist; &turn; NMR; peptide design; protein folding; side-chain interactionsThe mechanism by which a polypeptide chain folds into its native three-dimensional structure is still an open question. One of the proposed mechanisms, the framework model, includes secondary structure formation in the early steps of protein folding (Kim & Baldwin, 1990;Dyson &Wright, 1991. Extensive work on the conformational properties of protein fragments and designed peptides has been performed to gain insights into the factors responsible for the formation of secondary structure. A large body of information is now available about cy-helix formation and stability

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“…A centrally positioned D-Pro-Gly or D-Pro-Ala segment had been used to facilitate type IIЈ or type IЈ ␤-turn formations (12)(13)(14)(15). Initially the two strands of the ␤-hairpins for which crystals were obtained were composed of all ␣-amino acid residues (16)(17)(18).…”

mentioning

confidence: 99%

Infinite pleated β-sheet formed by the β-hairpin Boc-β-Phe-β-Phe- d -Pro-Gly-β-Phe-β-Phe-OMe

Karle

Gopi

Balaram

2002

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

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Stereochemical Requirements for β-Hairpin Formation: Model Studies with Four-Residue Peptides and Depsipeptides

Cited by 266 publications

References 45 publications

Length-dependent stability and strand length limits in antiparallel β-sheet secondary structure

Length-dependent stability and strand length limits in antiparallel β-sheet secondary structure

Cross‐strand side‐chain interactions versus turn conformation in β‐hairpins

Infinite pleated β-sheet formed by the β-hairpin Boc-β-Phe-β-Phe- d -Pro-Gly-β-Phe-β-Phe-OMe

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