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. 1992;114(13):5437-5439.
doi: 10.1021/ja00039a072.

Solvent Effects on the Energetics of Prolyl Peptide Bond Isomerization

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Free PMC article

Solvent Effects on the Energetics of Prolyl Peptide Bond Isomerization

Eric S Eberhardt et al. J Am Chem Soc. .
Free PMC article

Abstract

Racemic Ac-Gly-[β,δ-(13)C]Pro-OMe was synthesized, and the kinetics and thermodynamics of the isomerization of its prolyl peptide bond were determined in nine solvents by using NMR and IR spectroscopy. The free energy of activation is 1.3 kcal/mol larger in water than in aprotic solvents, and correlates with the ability of a solvent to donate a hydrogen bond but not with solvent polarity. These results are consistent with conventional pictures of amide resonance, which require transfer of charge between oxygen and nitrogen during isomerization. Similar medium effects may modulate the stability of planar peptide bonds in the active site of peptidyl-prolyl cis-trans isomerases (PPIases) and during the folding, function, or lysis of proteins.

Figures

Figure 1
Figure 1
Arrhenius plots for the cis to trans (A) and trans to cis (B) isomerizations of 1 in different solvents. Solvents (dielectric constant at 25°C) were as follows: ◇, dioxane (2.21); ○, benzene (2.27); ▽, toluene (2.38); ●, isopropyl alcohol (19.92); ■, ethanol (24.55); ◆, trifluoroethanol (26.14); □, acetonitrile (35.94); △, N,N-dimethylformamide (36.71); and formula image, water (78.30). Linear regression analysis is shown for each protic solvent (—) and all aprotic solvents (---).
Figure 2
Figure 2
Plots of ΔG for isomerization of 1 vs υ of amide I vibrational mode of Ac-Pro-OMe in different solvents. Symbols are as in Figure 1. Values of ΔG were calculated by interpolating the Arrhenius plots of Figure 1 at 60°C. Weighted linear regression analysis is shown for cis to trans [—, slope = − 0.025 ± 0.003 kcal·cm/mol] and trans to cis [---, slope = − 0.029 ± 0.002 kcal·cm/mol]. ΔGaprotic – ΔGwater = 1.3 ± 0.2 kcal/mol.
Equation 1
Equation 1

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