Context‐Dependence of the Contribution of Disulfide Bonds to β‐Hairpin Stability

Santiveri, Clara M.; León, Esther; Rico, Manuel; Jiménez, María Ángeles Sánchez

doi:10.1002/chem.200700845

Cited by 56 publications

(58 citation statements)

References 88 publications

(83 reference statements)

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“…This stabilization is larger than the effect of a covalent disulfide bond (∼4 kJ∕mol) (34). In the present study, stable hairpins of sequences Ac-W-ðZZÞ n -loop-ðZZÞ n -WTG-X (wherein the loop regions are four or more residues, the majority of the Z residues have some propensity for β-strand conformations, and X can be any amino acid residue or polypeptide extension) have been prepared for n ¼ 0;1;2, and 3.…”

Section: Discussionmentioning

confidence: 87%

Stabilizing capping motif for β-hairpins and sheets

Kier

Shu²,

Eidenschink³

et al. 2010

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

156

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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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Section: Discussionmentioning

confidence: 87%

Stabilizing capping motif for β-hairpins and sheets

Kier

Shu²,

Eidenschink³

et al. 2010

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

156

View full text Add to dashboard Cite

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“…The MD values for α are more frequently included in the 150° to 180° range exactly in the maximum potential energy region, but the values that are also observed in the 90° region coincide with the minimum of the α potential energy. These results indicate that two opposite effects are competing: the first is the natural tendency for α to assume values that reduce the corresponding potential energy, while the second effect is due to the inadequacy of the disulfide bridge to reduce the tensions in the CB(Cys2), SG(Cys2), SG(Cys2), CB(Cys15) and neighboring region (Santiveri et al, 2008). At this point, the two main consequences are the hindering of the natural tendency to decrease the torsion angle energy and the hindering of HB formation.…”

Section: Residuesmentioning

confidence: 99%

“…Indeed, it has been experimentally observed that the location of the disulfide bridges within the β-hairpin structure is a determinant factor for the β-hairpin stability only when disulfide bonds link originally non-hydrogen-bonded residues facing each other (Santiveri et al, 2008). Just in this case, do the disulfide bridges effectively contribute to the stabilization of the β-hairpin structure.…”

Section: Hydrogen Bonds Occurrence (%)mentioning

confidence: 99%

“…This is one more proof that the disulfide bridges within the β-hairpin structure are a determinant factor for the β-hairpin stability only when disulfide bonds link originally non-hydrogen-bonded residues. The multimodal distributions of the Ramachandran angles are a consequence of the inadequacy of the disulfide bridge to reduce the tensions in its neighboring region (Santiveri et al, 2008).…”

Section: The Ramachandran Anglesmentioning

confidence: 99%

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The role of disulfide bridges in the 3-D structures of the antimicrobial peptides gomesin and protegrin-1: a molecular dynamics study

Castro¹,

Fuzo²,

Degrève³

et al. 2008

Genet. Mol. Res.

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ABSTRACT. Some antimicrobial peptides have a broad spectrum of action against many different kinds of microorganisms. Gomesin and protegrin-1 are examples of such antimicrobial peptides, and they were studied by molecular dynamics in this research. Both have a β-hairpin conformation stabilized by two disulfide bridges and are active against Gram-positive and Gram-negative bacteria, as well as fungi. In this study, the role of the disulfide bridge in the maintenance of the tertiary peptide structure of protegrin-1 and gomesin is analyzed by the structural characteristics of these peptides and two of their respective variants, gomy4 and proty4, in which the four cysteines are replaced by four tyrosine residues. The absence of disulfide bridges in gomy4 and proty4 is compensated by overall reinforcement of the original hydrogen bonds and extra attractive interactions between the aromatic rings of the tyrosine residues. The net effects on the variants with respect to the corresponding natural peptides are: i) maintenance of the original β-hairpin conformation, with great structural similarities between the mutant and the corresponding natural peptide; ii) combination of positive Φ and Ψ Ra- Role of disulfide bridges in gomesin and protegrin-1 machandran angles within the hairpin head region with a qualitative change to a combination of positive (Φ) and negative (Ψ) angles, and iii) significant increase in structural flexibility. Experimental facts about the antimicrobial activity of the gomesin and protegrin-1 variants have also been established here, in the hope that the detailed data provided in the present study may be useful for understanding the mechanism of action of these peptides.

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“…From the standpoint of immunogen design, some means of rigidifying the V1V2 backbone to induce an intrinsic β-preference would be desirable for targeting the subdominant BnAb response. A seemingly straightforward strategy would involve cyclization using an intramolecular disulfide linkage (36). In this regard, Amin et al recently reported the synthesis of monomeric cyclic V2 peptides with glycans at N 160 and N 156 /N 173 (37).…”

Section: Discussionmentioning

confidence: 99%

Recognition of synthetic glycopeptides by HIV-1 broadly neutralizing antibodies and their unmutated ancestors

Alam

Dennison

Aussedat

et al. 2013

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

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Current HIV-1 vaccines elicit strain-specific neutralizing antibodies. Broadly neutralizing antibodies (BnAbs) are not induced by current vaccines, but are found in plasma in ∼20% of HIV-1-infected individuals after several years of infection. One strategy for induction of unfavored antibody responses is to produce homogeneous immunogens that selectively express BnAb epitopes but minimally express dominant strain-specific epitopes. Here we report that synthetic, homogeneously glycosylated peptides that bind avidly to variable loop 1/2 (V1V2) BnAbs PG9 and CH01 bind minimally to strain-specific neutralizing V2 antibodies that are targeted to the same envelope polypeptide site. Both oligomannose derivatization and conformational stabilization by disulfide-linked dimer formation of synthetic V1V2 peptides were required for strong binding of V1V2 BnAbs. An HIV-1 vaccine should target BnAb unmutated common ancestor (UCA) B-cell receptors of naïve B cells, but to date no HIV-1 envelope constructs have been found that bind to the UCA of V1V2 BnAb PG9. We demonstrate herein that V1V2 glycopeptide dimers bearing Man 5 GlcNAc 2 glycan units bind with apparent nanomolar affinities to UCAs of V1V2 BnAbs PG9 and CH01 and with micromolar affinity to the UCA of a V2 strainspecific antibody. The higher-affinity binding of these V1V2 glycopeptides to BnAbs and their UCAs renders these glycopeptide constructs particularly attractive immunogens for targeting subdominant HIV-1 envelope V1V2-neutralizing antibody-producing B cells.

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Context‐Dependence of the Contribution of Disulfide Bonds to β‐Hairpin Stability

Cited by 56 publications

References 88 publications

Stabilizing capping motif for β-hairpins and sheets

Stabilizing capping motif for β-hairpins and sheets

The role of disulfide bridges in the 3-D structures of the antimicrobial peptides gomesin and protegrin-1: a molecular dynamics study

Recognition of synthetic glycopeptides by HIV-1 broadly neutralizing antibodies and their unmutated ancestors

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