Insights on β-Hairpin Stability in Aqueous Solution from Peptides with Enforced Type I‘ and Type II‘ β-Turns

Haque, Tasir S.; Gellman, Samuel H.

doi:10.1021/ja963653h

Cited by 249 publications

(243 citation statements)

References 25 publications

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“…This turn, lacking the correct geometry for the right-handed twist, does not allow an optimal packing of side chains. Thus, intrinsic conformational properties of the turn backbone seem to be more important in P-hairpin conformation and stability than particular patterns of cross-strand side-chain interactions, in agreement with our previous results (de Alba et al, 1996Alba et al, , 1997 and those of Haque and Gellman (1997) using a different peptide system. On the basis of the structures of our peptides and those of protein @hairpins 3:5 and 4:4, a clear relationship appears to exist between the conformation of the turn and the P-hairpin twist, in the sense that the type I + GI P-bulge turn favors the right-handed twist, whereas the regular type I turn does not.…”

Section: Resultssupporting

confidence: 92%

“…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%

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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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Section: Resultssupporting

confidence: 92%

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

confidence: 99%

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

1997

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“…All of these spectroscopic features could be used as probes to determine fold population (χ F ). * Gly4 to L-Ala and D-Ala mutations (SI Appendix) had negligible effects on fold stability of Ac-WIpGKWTG-NH 2 even though these enforce type II′ and I′ turns, respectively (6,32). This indifference to turn type prompted us to view Ac-W --WTG as a general capping motif and to examine its efficacy at positions remote from the turn.…”

Section: Resultsmentioning

confidence: 99%

“…The key discoveries that improved β-hairpin stabilities outside of protein contexts have been sequences with good turn propensities, for example D-Pro-Gly (pG) (6), heterochiral pP (7), and Aib-Gly (8) [or less favorably, Asn-Gly (NG) (5,9)] and the incorporation of optimized cross-strand pairings [most notably Trp/Trp pairs flanking the turn (10)(11)(12)(13)(14)]. However, longer hairpin models are typically still frayed at the termini; to date, fully folded spectroscopic reference values have only been attained via cyclization (15)(16)(17).…”

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confidence: 99%

Stabilizing capping motif for β-hairpins and sheets

Kier

Shu²,

Eidenschink³

et al. 2010

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

158

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Although much has been learned about the design of models of β-sheets during the last decade, modest fold stabilities in water and terminal fraying remain a feature of most β-hairpin peptides. In the case of hairpin capping, nature did not provide guidance for solving the problem. Some observations from prior turn capping designs, with further optimization, have provided a generally applicable, "unnatural" beta cap motif (alkanoyl-Trp at the N terminus and Trp-Thr-Gly at the C terminus) that provides a net contribution of 6 þ kJ∕mol to β-hairpin stability, surpassing all other interactions that stabilize β-hairpins including the covalent disulfide bond. The motif, made up entirely of natural residues, is specific to the termini of antiparallel β-strands and reduces fraying at the ends of hairpins and other β-sheet models. Utilizing this motif, 10-to 22-residue peptide scaffolds of defined stereochemistry that are greater than 98% folded in water have been prepared. The β-cap can also be used to staple together short antiparallel β-strands connected by a long flexible loop.beta sheets | capping stabilization | peptide hairpins | Trp/Trp interactions C apping motifs are well-known features of protein and peptide secondary structure; specifically, terminal alpha helix caps (especially N caps) are common both in proteins and designed peptides (1-4). The basis for helix capping is straightforward: countering the helix macrodipole and providing additional H-bonding interactions (1). Caps increase the fold population of isolated α-helical peptides and have been a boon to the design of α-helix models. β-Structures have capping requirements wholly different from those of helices; the ends of canonical β-sheets and hairpins do not have dipole moments or unsatisfied H bonds.The a priori design of model β-sheet systems (5), focused on hairpins, has lagged behind that of α-helix counterparts. The key discoveries that improved β-hairpin stabilities outside of protein contexts have been sequences with good turn propensities, for example D-Pro-Gly (pG) (6), heterochiral pP (7), and Aib-Gly (8) [or less favorably, Asn-Gly (NG) (5, 9)] and the incorporation of optimized cross-strand pairings [most notably Trp/Trp pairs flanking the turn (10-14)]. However, longer hairpin models are typically still frayed at the termini; to date, fully folded spectroscopic reference values have only been attained via cyclization (15-17). With the exception of cyclization, mutations at terminal sites have yielded only modest changes in hairpin stability; terminal coulombic effects (ΔΔG U ¼ 1.5-2.5 kJ∕mol) standing as the only generally observed capping effect (11,18,19). Pi-cation interactions have also been shown to provide significant hairpin stabilization (20), but instances in which the interaction appears near the ends of hairpins have provided only marginal stability increases (18,(21)(22)(23)). An unnatural π-cation interaction has also been shown to stabilize the turn in a tripeptide (24). There has been limited evidence for hairpin fold sta...

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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%