Polymer Principles of Protein Calorimetric Two-State Cooperativity

Abstract

The experimental calorimetric two-state criterion requires the van't Hoff enthalpy $\Delta H_{\mathrm{vH}}$ around the folding/unfolding transition midpoint to be equal or very close to the calorimetric enthalpy $\Delta H_{\mathrm{cal}}$ 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 $\Delta H_{\mathrm{vH}}$'s being approximately equal to $\Delta H_{\mathrm{cal}}$ 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'' $T_{\mathrm{f}}/T_{\mathrm{g}}$ 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.

arXiv comment27 pages, 15 postscripts figures. Accepted for publication in Proteins: Struct. Funct. Genet