Polymer Principles of Protein Calorimetric Two-State Cooperativity

Abstract

The experimental calorimetric two-state criterion requires the van't Hoff enthalpy $ΔH_{\rm vH}$ around the folding/unfolding transition midpoint to be equal or very close to the calorimetric enthalpy $ΔH_{\rm cal}$ of the entire transition. We use an analytical model with experimental parameters from chymotrypsin inhibitor 2 to elucidate the relationship among several different van't Hoff enthalpies used in calorimetric analyses. Under reasonable assumptions, the implications of these $ΔH_{\rm vH}$'s being approximately equal to $ΔH_{\rm cal}$ are equivalent: Enthalpic variations among denatured conformations in real proteins are much narrower than some previous lattice-model estimates, suggesting that the energy landscape theory ``folding to glass transition temperature ratio'' $T_{\rm f}/T_{\rm g}$ may exceed 6.0 for real calorimetrically two-state proteins. Several popular three-dimensional lattice protein models, with different numbers of residue types in their alphabets, are found to fall short of the high experimental standard for being calorimetrically two-state. Some models postulate a multiple-conformation native state with substantial pre-denaturational energetic fluctuations well below the unfolding transition temperature and/or predict a significant post-denaturational continuous conformational expansion of the denatured ensemble at temperatures well above the transition point.