Dissecting the stability of a β-hairpin peptide that folds in water: NMR and molecular dynamics analysis of the β-turn and β-strand contributions to folding 1 1Edited by P. E. Wright

Griffiths-Jones, Sam; Maynard, Allister J.; Searle, Mark S.

doi:10.1006/jmbi.1999.3119

Cited by 168 publications

(207 citation statements)

References 95 publications

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“…In fact the predominate effect of TFE on BET and BHA seems to be in the stabilization of the turn regions. The importance of turn regions in determining the folding and the stability of ␤-forming structures has been shown by several groups (35,41,42), and the selective stabilization of turn regions by TFE has been demonstrated by several recent NMR studies (34,35,41), which certainly could in part account for the effect of TFE on the stability ␤-sheet-forming peptides.…”

Section: Discussionmentioning

confidence: 94%

See 1 more Smart Citation

Mechanism by which 2,2,2-trifluoroethanol/water mixtures stabilize secondary-structure formation in peptides: A molecular dynamics study

Roccatano

Colombo

Fioroni

et al. 2002

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

473

452

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Molecular dynamics simulation techniques have been used to investigate the effect of 2,2,2-trifluoroethanol (TFE) as a cosolvent on the stability of three different secondary structure-forming peptides: the ␣-helix from Melittin, the three-stranded ␤-sheet peptide Betanova, and the ␤-hairpin 41-56 from the B1 domain of protein G. The peptides were studied in pure water and 30% (vol͞vol) TFE͞water mixtures at 300 K. The simulations suggest that the stabilizing effect of TFE is induced by the preferential aggregation of TFE molecules around the peptides. This coating displaces water, thereby removing alternative hydrogen-bonding partners and providing a low dielectric environment that favors the formation of intrapeptide hydrogen bonds. Because TFE interacts only weakly with nonpolar residues, hydrophobic interactions within the peptides are not disrupted. As a consequence, TFE promotes stability rather than inducing denaturation. F or more than three decades, 2,2,2-trifluoroethanol (TFE) has been used as a cosolvent for the study of peptides in solution because NMR and CD studies show that the presence of TFE increases the population of ␣-helix and ␤-sheet content in secondary-structure-forming peptides in TFE͞water mixtures (1-3). Despite the effects of TFE having been known for such a long time, the mechanism by which TFE stabilizes secondary structure in peptides is still not clear. One possible explanation is the preferential solvation of the folded state by TFE (3). According to this hypothesis, TFE acts within the context of a preexisting helix-coil equilibrium, and the preferential interaction of TFE with the folded state shifts the equilibrium toward more structured conformations (3). The molecular nature of the TFE-peptide interaction is not clear, however. Alternative mechanisms have also been proposed to explain the stabilizing effect of TFE. In particular, the effect could result from TFE reinforcing hydrogen bonds between carbonyl and amidic NH groups by the removal of water molecules in the proximity of the solute (4) and͞or the lowering of the dielectric constant (1). Furthermore, small-angle x-ray-scattering studies (2) show that TFE forms clusters in water as the concentration of the organic cosolvent is increased, with a maximum at 30% (vol͞vol) TFE. Reiersen and Rees (5) have proposed that such TFE clusters locally assist the folding of secondary-structure elements by providing a solvent matrix that promotes hydrophobic interactions between amino acid side chains. Recent NMR studies involving small peptides in TFE provide some support for this hypothesis (6-8). Each of these mechanisms could explain the stabilization of ␣-helical peptides in solution (1, 3) but not necessarily the stabilization of ␤-structure (1, 2).In recent years molecular dynamics (MD) simulations have been increasingly used to understand the complex conformational equilibria of polypeptides in solution and to predict structural preferences (9-11). In particular, the importance of side-chain interactions in determining pepti...

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Section: Discussionmentioning

confidence: 94%

“…Whereas in TFE͞water the geometry of the turn is well conserved throughout the simulation, in water the turn geometry fluctuates being recognized approximately a third of the time as the bend. These fluctuations are in turn related to the twisting of the peptide (9,34,35).…”

Section: Resultsmentioning

confidence: 99%

Mechanism by which 2,2,2-trifluoroethanol/water mixtures stabilize secondary-structure formation in peptides: A molecular dynamics study

Roccatano

Colombo

Fioroni

et al. 2002

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

473

452

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“…The β-hairpin conformation, being the simplest antiparallel β-sheet and one of the principal secondary structural elements of proteins, has been studied extensively in experiments [42][43][44][45][46][47][48] and computer simulations. [49][50][51][52] Previous results have led to two primary hypothesis for the formation of a β-hairpin: one in which the structure is initiated at the turn (zipping mechanism), and another in which a hydrophobic cluster first forms first (hydrophobic collapse mechanism).…”

Section: Introductionmentioning

confidence: 99%

α-helix to β-hairpin transition of human amylin monomer

Singh

Chiu

Reddy

et al. 2013

The Journal of Chemical Physics

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The human islet amylin polypeptide is produced along with insulin by pancreatic islets. Under some circumstances, amylin can aggregate to form amyloid fibrils, whose presence in pancreatic cells is a common pathological feature of Type II diabetes. A growing body of evidence indicates that small, early stage aggregates of amylin are cytotoxic. A better understanding of the early stages of the amylin aggregation process and, in particular, of the nucleation events leading to fibril growth could help identify therapeutic strategies. Recent studies have shown that, in dilute solution, human amylin can adopt an α-helical conformation, a β-hairpin conformation, or an unstructured coil conformation. While such states have comparable free energies, the β-hairpin state exhibits a large propensity towards aggregation. In this work, we present a detailed computational analysis of the folding pathways that arise between the various conformational states of human amylin in water. A free energy surface for amylin in explicit water is first constructed by resorting to advanced sampling techniques. Extensive transition path sampling simulations are then employed to identify the preferred folding mechanisms between distinct minima on that surface. Our results reveal that the α-helical conformer of amylin undergoes a transformation into the β-hairpin monomer through one of two mechanisms. In the first, misfolding begins through formation of specific contacts near the turn region, and proceeds via a zipping mechanism. In the second, misfolding occurs through an unstructured coil intermediate. The transition states for these processes are identified. Taken together, the findings presented in this work suggest that the inter-conversion of amylin between an α-helix and a β-hairpin is an activated process and could constitute the nucleation event for fibril growth.

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“…b-Hairpin motifs differ in the length of the turn region and are classified according to the number of turn residues and the hydrogen bond pattern of residues flanking the turn~Sibanda & Thornton, 1985Thornton, , 1991Sibanda et al, 1989!. Several studies on model peptides highlighted the importance of the turn region in determining b-hairpin stability~Ramírez- Alvarado et al, 1997;Blanco et al, 1998;Gellman, 1998;Griffiths-Jones et al, 1999!. Moreover, the NMR investigation of a series of model b-hairpinforming peptides~de Alba et al, 1996Alba et al, , 1997aAlba et al, , 1999a showing that they were able to adopt different b-hairpin structures when differing only on their turn sequence, demonstrated that the turn sequence determines the b-strand alignment in the b-hairpin. Further evidence came from ubiquitin-derived peptides that showed different strand register depending on the turn residues~Searle et Haque & Gellman, 1997!.…”

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confidence: 99%

Position effect of cross‐strand side‐chain interactions on β‐hairpin formation

2000

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Previous conformational analysis of 10-residue linear peptides enabled us to identify some cross-strand side-chain interactions that stabilize b-hairpin conformations. The stabilizing influence of these interactions appeared to be greatly reduced when the interaction was located at the N-and C-termini of these 10-residue peptides. To investigate the effect of the position relative to the turn of favorable interactions on b-hairpin formation, we have designed two 15-residue b-hairpin forming peptides with the same residue composition and differing only in the location of two residues within the strand region. The conformational properties of these two peptides in aqueous solution were studied by 1 H and 13 C NMR. Differences in the conformational behavior of the two designed 15-residue peptides suggest that the influence of stabilizing factors for b-hairpin formation, in particular, cross-strand side-chain interactions, depends on their proximity to the turn. Residues adjacent to the turn are most efficient in that concern. This result agrees with the proposal that the turn region acts as the driving force in b-hairpin folding.Keywords: b-hairpin; b-turn; NMR; peptide design; protein folding; side-chain interactions Understanding the forces that govern the formation and stability of secondary structure is essential for the rational and successful de novo design of proteins. Analysis of the conformational behavior of protein fragments and designed peptides has provided a large amount of information on the formation and stability of a-helices

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Dissecting the stability of a β-hairpin peptide that folds in water: NMR and molecular dynamics analysis of the β-turn and β-strand contributions to folding 1 1Edited by P. E. Wright

Cited by 168 publications

References 95 publications

Mechanism by which 2,2,2-trifluoroethanol/water mixtures stabilize secondary-structure formation in peptides: A molecular dynamics study

Mechanism by which 2,2,2-trifluoroethanol/water mixtures stabilize secondary-structure formation in peptides: A molecular dynamics study

α-helix to β-hairpin transition of human amylin monomer

Position effect of cross‐strand side‐chain interactions on β‐hairpin formation

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