Mechanism of Helix Induction by Trifluoroethanol:  A Framework for Extrapolating the Helix-Forming Properties of Peptides from Trifluoroethanol/Water Mixtures Back to Water

Abstract

To establish a framework for extrapolating the helix-forming properties of peptides from TFE/H2O mixtures (TFE = 2,2, 2-trifluoroethanol) back to water, the thermal unfolding curves have been measured by circular dichroism for four repeating-sequence peptides, with chain lengths from 7 to 22 residues. The unfolding curves were measured between 0 and 50 volume percent TFE and were fitted to the modified Lifson-Roig theory. A single set of helix-coil parameters fits the results for the four peptides at each TFE concentration; only two of the basic helix-coil parameters, <w>, the mean helix propagation parameter of residues in the sequence repeat, and DeltaH, the enthalpy change per residue on unfolding the helix, are allowed to vary with TFE molarity. The success in fitting these curves over a wide range of experimental variables shows that helix formation is basically the same in TFE/H2O mixtures as in water. Moreover, a simple model based on a linear dependence of ln <w> and DeltaH on TFE molarity can be used to extrapolate the results from 25% TFE (approximately 4 M) back to water. The results also give curves of helix formation induced by TFE at constant temperature, and the properties of these helix induction curves explain some of the puzzling results shown by other peptides in the literature. The average helix propensity increases regularly from 0 to 25% TFE but levels off at higher TFE concentrations, which explains why the extent of helix formation levels off in this range. The change in the apparent cooperativity of thermal unfolding curves in concentrated TFE solutions results from the decrease of the enthalpy change for helix unfolding at higher TFE concentrations. The rapid decrease in the plateau values of apparent helix content with increasing temperature results mainly from the strong temperature dependence of the ellipticity of the complete helix. To determine whether the helix-stabilizing effect of TFE arises from strengthening the hydrogen bonds in the helix backbone, the strength of the hydrogen bond in a model compound, salicylic acid, has been measured in TFE/H2O mixtures from the pKa difference between salicylic acid and a similar compound which cannot form the hydrogen bond. The curve of hydrogen bond strength versus increasing TFE concentration matches both in shape and magnitude the increase in average helix propensity in TFE/H2O mixtures.

Helicity of short E‐R/K peptides

“…22 The 1974 Chen equation for calculating percent helix values was later tested with Ala-based peptides of varying chain lengths and was refined slightly. 26 In the case of the E4K4 peptide, the helix content is high at 59%, close to the value predicted by the AGADIR algorithm (Table I). …”

Peptide-tethered monodentate and chelating histidylidene metal complexes: synthesis and application in catalytic hydrosilylation

“…Thus deprotection of the alanine dipeptide Boc-Ala 2 - 20 OMe or tripeptide Boc-Ala 3 -OMe at the C-terminus using LiOH followed by careful neutralisation and subsequent coupling to the free amine 2 yielded the oligopeptides 3a-b. Even though both routes gave the desired oligopeptides 3 in the same number of steps, route B presents the significant advantage to be convergent 25 rather than a completely linear reaction sequence. The imidazole ring was then alkylated by gently heating 3 with MeI in MeCN to give the N δ ,N ε -dimethylated histidinium oligopeptides Boc-Ala nHis*-OMe 4a (n = 2) and 4b (n = 3).…”

“…12 An alanine dipeptide linker was placed between the coordination sites in order to promote the formation of an α-helix. 21 Since a complete turn in a peptidic α-helix contains 3.6 amino acid 25 residues, the resulting tetrapeptides may adopt a conformation that is suitable for chelation where the side chain of the i+3 residue (i.e. Met/Tyr) is positioned almost eclipsed to the metalbound histidylidene unit.…”

“…In addition, imidazole and its substituted derivatives constitute versatile precursors for the formation of N-heterocyclic carbenes (NHCs), a powerful class of spectator ligands for transition metal chemistry. 2 Hence, modification of histidine to a NHC precursor 25 provides a straightforward approach to bioorganometallic chemistry, 3 as the metal-carbene complex enables the exploitation of typical organometallic function such as catalysis, while the peptidic backbone offers opportunities for peptidic transformations and hence biochemical engineering of the 30 hybride. For example, specific structural conformations may be induced that affect the organometallic site.…”

α-Helix Formation in Melittin and β-Lactoglobulin A Induced by Fluorinated Dialcohols

“…17 It has been shown that for some repeating-sequence peptides, containing mainly alanine residues, the presence of TFE strengthens hydrogen bonds within the helical state to an extent sufficient to account for the increase in helix propensity in the presence of TFE. 18 An indirect mechanism may be involved in which peptide hydrogen bonds to the solvent are weakened in conjunction with lowering of the solvent dielectric constant. 19-21,1 Alternatively, helicogenic enhancement may occur by a direct mechanism involving preferential solvation of the polypeptide and direct binding of TFE to the polypeptide chain in the so-called helical state.…”