Structure and dynamics regulate protein function, but much less is known about how biomoleculesolvent interactions affect the structure-function relationship. Even less is known about the thermodynamics of biomolecule-solvent interactions and how such interactions influence conformational entropy. When transferred from propanol into 40:60 propanol:water under acidic conditions, a remarkably slow protonation reaction coupled with the conversion of the polyproline-I helix (PPI, having all cis-configured peptide bonds) into polyproline-II (PPII, all trans) helix is observed in this work. Kinetics and equilibrium measurements as a function of temperature allow determination of the thermochemistry and insight into how proton transfer is regulated in this system. For the proton-transfer process, PPIPrOH+ + H3O+ -> PPIIPrOH/aq2+ + H2O, we determine Delta G = -20 +/- 19 kJ.mol(-1), Delta H = -75 +/- 14 kJ.mol(-1), and Delta S= -188 +/- 48 J.mol(-1).K-1 for the overall reaction, and values of Delta G(double dagger) = 91 +/- 3 kJ.mol(-1), Delta H-double dagger = 84 +/- 9 kJ.mol(-1), and ?S-double dagger = -23 +/- 31 J.mol(-1).K-1 for the transition state. For a minor process, PPIPrOH+ -> PPIIPrOH/aq+ without protonation, we determine Delta G = -9 +/- 20 kJ.mol(-1), Delta H = 64 +/- 14 kJ.mol(-1), and Delta S= 247 +/- 50 J.mol(-1).K-1. This thermochemistry yields Delta G = -10 +/- 29 kJ.mol(-1), Delta H = -139 +/- 20 kJ.mol(-1), and Delta S= -435 +/- 70 J.mol(-1).K-1 for PPIIPrOH/aq+ + H3O+ -> PPIIPrOH/aq2+ +H2O. The extraordinarily slow proton transfer appears to be an outcome of configurational coupling through a PPI-like transition state.