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JOURNAL ARTICLE

Conformational changes of trialanine induced by direct interactions between alanine residues and alcohols in binary mixtures of water with glycerol and ethanol

Siobhan Toal, Omid Amidi, Reinhard Schweitzer-Stenner
Journal of the American Chemical Society 2011 August 17, 133 (32): 12728-39
21728315
Despite the increasing relevance of characterizing local conformational distributions in the unfolded state, an unambiguous description of the role that solvation and the addition of certain cosolvents play in altering this ensemble has yet to emerge. Alcohol cosolvents, and specifically glycerol, are known to act as protein stabilizers. The underlying mechanism of this effect is, however, still debated. Short alanine-based peptides provide a suitable model system for exploring the influence of cosolvents on backbone conformations, as ample experimental evidence now indicates that alanine does not exhibit a true statistical coil behavior but rather shows strong preference for sampling the polyproline II (PPII) region of the Ramachadran map when solvated in water. To explore the effect glycerol and ethanol cosolvents have on the conformational distribution of trialanine, we combined UV-CD and H NMR spectroscopies. The temperature dependence of the conformationally sensitive maximum dichroism (Δε) and (3)J(H(α)H(N)) coupling constants of two amide protons (N- and C-terminal) was subjected to a global thermodynamic analysis based on simple two-state PPII↔β models. Interestingly, our results show that even small admixtures of alcohol (5% v/v) considerably change the spectral parameters, Δε(PPII) and Δε(β), as well as the enthalpic and entropic differences between the two states. For the central residue of trialanine in 5% glycerol, we obtained a gain in enthalpy favoring PPII of ΔΔH(n) = -4.80 kJ/mol and a compensating increase in entropy favoring the β-strand of ΔΔS(n) = -13.53[J/mol K]. This causes increases in -ΔG and slight increases in PPII content. Further addition of alcohol, however, reverses the trend in that it causes a destabilization of the hydration shell and a shift toward β-strand conformations. The combined manifold of ΔH and ΔS values obtained for the investigated binary mixtures and the pure aqueous solvent exhibits an excellent linear correlation, which reflects enthalpy-entropy compensation and a common transition temperature. The latter can be considered an indication of a weak binding between cosolvent and peptide. A comparison of infrared and Raman spectra of trialanine in water and in water-alcohol mixtures indeed reveals a close proximity between aliphatic side chains of alanine residues and alcohol molecules even for 5% (v/v) alcohol-water mixtures. Hence, our results provide the first experimental evidence for direct interactions between, e.g., glycerol and peptides in aqueous solutions, in line with the result of recent calculations by Vagenende et al. (Biochemistry 2009, 48, 11084-11096) but at variance with preferential exclusion theories.

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