title: Solvation effects and driving forces for protein thermodynamic and kinetic cooperativity: how adequate is native-centric topological modeling?
abstract: What energetic and solvation effects underlie the remarkable two-state thermodynamics and folding/unfolding kinetics of small single-domain proteins? To address this question, we investigate the folding and unfolding of a hierarchy of continuum Langevin dynamics models of chymotrypsin inhibitor 2. We find that residue-based additive Gō-like contact energies, although native-centric, are by themselves insufficient for protein-like calorimetric two-state cooperativity. Further native biases by local conformational preferences are necessary for protein-like thermodynamics. Kinetically, however, even models with both contact and local native-centric energies do not produce simple two-state chevron plots. Thus a model protein's thermodynamic cooperativity is not sufficient for simple two-state kinetics. The models tested appear to have increasing internal friction with increasing native stability, leading to chevron rollovers that typify kinetics that are commonly referred to as non-two-state. The free energy profiles of these models are found to be sensitive to the choice of native contacts and the presumed spatial ranges of the contact interactions. Motivated by explicit-water considerations, we explore recent treatments of solvent granularity that incorporate desolvation free energy barriers into effective implicit-solvent intraprotein interactions. This additional feature reduces both folding and unfolding rates vis-à-vis that of the corresponding models without desolvation barriers, but the kinetics remain non-two-state. Taken together, our observations suggest that interaction mechanisms more intricate than simple Gō-like constructs and pairwise additive solvation-like contributions are needed to rationalize some of the most basic generic protein properties. Therefore, as experimental constraints on protein chain models, requiring a consistent account of protein-like thermodynamic and kinetic cooperativity can be more stringent and productive for some applications than simply requiring a model heteropolymer to fold to a target structure.
authors.affiliation: Department of Biochemistry, Protein Engineering Network of Centres of Excellence (PENCE), Faculty of Medicine, University of Toronto, Toronto, Ont., Canada M5S 1A8.
authors.forename: Hüseyin
authors.initials: H
authors.lastname: Kaya
authors.forename: Hue Sun
authors.initials: HS
authors.lastname: Chan
mesh_terms: D002151:Calorimetry; D007700:Kinetics; D008958:Models, Molecular; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry*; D012997:Solvents / Q000737:chemistry*; D013816:Thermodynamics
chemical_list: D011506:Proteins; D012997:Solvents