An Indirect Chaotropic Mechanism for the Stabilization of Helix Conformation of Peptides in Aqueous Trifluoroethanol and Hexafluoro-2-propanol

Walgers, Richard; Lee, Tony C.; Cammers‐Goodwin, Arthur

doi:10.1021/ja973552z

Cited by 100 publications

(92 citation statements)

References 39 publications

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“…By aggregating around the solute the TFE molecules exclude water, favoring the formation of intramolecular hydrogen bonds and promoting the formation of secondary structure. This result is similar to the indirect chaotropic mechanism of Walgers et al (44). At the same time, TFE, despite having a lower dielectric constant than water, does not significantly disrupt hydrophobic interactions, which are important in the stability of both BHA and BET.…”

Section: Discussionsupporting

confidence: 88%

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.

478

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: Discussionsupporting

confidence: 88%

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.

478

452

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“…Interestingly, the fluorine-containing alcohols trifluoroethanol and hexfluoroisopropanol both solubilize 1 showing absorption ratios greater than acetonitrile, indicating an increased destabilization of the helical conformation. Recent studies of ␣-peptides in mixtures of water and fluorinated solvents demonstrated stabilization of helical conformations, wherein the fluorine segments of the solvents created solvation shells around the hydrophobic solute (40,41). Similar solvent-backbone interactions may be operative with 1, in this case destabilizing the folded conformation, because fluorine-containing alcohols can solvate the oligomer, whereas their hydrogen-containing solvent counterparts cannot.…”

Section: Discussionmentioning

confidence: 99%

Helicogenicity of solvents in the conformational equilibrium of oligo(m-phenylene ethynylene)s: Implications for foldamer research

Hill

Moore

2002

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

135

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A (R)-binaphthol tethered bis-hexameric oligo(m-phenylene ethynylene) foldamer was examined in 30 solvents to correlate the unfolded-folded conformational equilibrium to bulk solvent properties and specific solvent-chain interactions. The oligomer is soluble in a variety of solvents of intermediate polarity, with the majority of these solvents being helicogenic. The amphiphilic nature of the chain allows the solvophobic backbone to be solubilized in a wide range of solvents through the polar triethylene glycol side chains. As demonstrated through UV and CD spectroscopic experiments, the helical conformation is increasingly stabilized with increasing solvent polarity in the absence of specific solvent-chain interactions. Surprisingly, very few solvents are capable of fully denaturing the helix, indicating the strength of the solvophobic driving forces in this cooperative system. The folding reaction for this amphiphilic oligomer can be described as a compromise in solubility properties, where chains collapse intramolecularly into helical conformations to minimize solventbackbone contacts while maintaining favorable solvent-side chain interactions for solvation. In terms of mimicking the properties of biomacromolecules, foldamers using solvophobic driving forces must be tempered with functionalities that promote solubility of the folded state while at the same time allowing access to the unfolded state through the use of denaturants.

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“…The cross peaks between water and H/H signals (CH, CH 2 , or CH 3 ) can be attributed unambiguously to NOE, while the cross peaks between water and HN might originate from either NOE or exchange. Both NOE and exchange imply that water molecules interact with peptides through direct binding possibly accompanied by water/HN exchange in 40% HFIP-d 2 aqueous solutions and HFIP may function as an indirect mechanism 42,43 to induce the formation of helical structure. Based on this observation, a value of 0.4 was used for 1 (see Materials And Methods).…”

Section: Self-assemblymentioning

confidence: 99%

HFIP‐induced structures and assemblies of the peptides from the transmembrane domain 4 of membrane protein Nramp1

Xue

Wang

et al. 2006

Biopolymers

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Membrane protein Nramp1 (natural resistance-associated macrophage protein 1) is a pH-dependent divalent metal cation transporter that regulates macrophage activation in infectious and autoimmune diseases. A naturally occurring glycine to aspartic acid substitution at position 169 (G169D) within the transmembrane domain 4 (TM4) of Nramp1 makes mice susceptible to Leishmania donovani, Salmonella typhimurium, and Mycobacterium bovis. Here we present a structural and self-assembling study on two synthetic 24-residue peptides, corresponding to TM4 of mouse Nramp1 and its G169D mutant, respectively, in 1,1,1,3,3,3-hexafluoroisopropanol-d(2) (HFIP-d(2)) aqueous solution by nuclear magnetic resonance (NMR) spectroscopy. The results show that amphipathic alpha-helical structures are formed from residue Ile173 to Tyr187 for the wild-type peptide and from Trp168 to Tyr187 for the G169D mutant, respectively. The segment of the N-terminus from Leu167 to Leu172 is poorly structured for the wild-type peptide, whereas it is well defined for the G169D mutant. Both peptides aggregate to form a tetramer and the monomeric peptides in peptide bundles are structurally and orientationally similar. The intermolecular interactions in assemblies could be stronger in the C-terminal regions related to residues Phe180-Leu184 than those in the central helical segments for both peptides. The G169D mutation may change the size of the opening on the termini of assembly.

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An Indirect Chaotropic Mechanism for the Stabilization of Helix Conformation of Peptides in Aqueous Trifluoroethanol and Hexafluoro-2-propanol

Cited by 100 publications

References 39 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

Helicogenicity of solvents in the conformational equilibrium of oligo(m-phenylene ethynylene)s: Implications for foldamer research

HFIP‐induced structures and assemblies of the peptides from the transmembrane domain 4 of membrane protein Nramp1

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