COOPERATIVITY IN PROTEIN-FOLDING - FROM LATTICE MODELS WITH SIDE-CHAINS TO REAL PROTEINS

Background: Over the past few years novel folding mechanisms of globul ar proteins have been proposed using minimal lattice and off-lattice m odels. The factors determining the cooperativity of folding in these m odels and especially their explicit relation to experiments have not b een fully established, however. Results: We consider equilibrium foldi ng transitions in lattice models with and without sidechains. A dimens ionless measure, Omega(c), is introduced to quantitatively assess the degree of cooperativity in lattice models and in real proteins. We sho w that larger values of Omega(c) resembling the values seen in protein s are obtained in lattice models with sidechains. The enhanced coopera tivity of such models results from possible denser packing of sidechai ns in the interior of the model polypeptide chain. We also establish t hat Omega(c) correlates extremely well with sigma(T) = (T-theta - T-f) /T-theta, where T-theta and T-f are collapse and folding transition te mperatures, respectively. These theoretical ideas are used to analyze folding transitions in two-state folders (RNase A, chymotrypsin inhibi tor 2, fibronectin type III modules and tendamistat) and three-state f olders (apomyoglobin and lysozyme). The values of Omega(c) extracted f rom experiments show a correlation with sigma(T) (suitably generalized when folding is induced by denaturants or acid). Conclusions: A quant itative description of the cooperative transition of real proteins can be made by lattice models with sidechains. The degree of cooperativit y in minimal models and real proteins can be expressed in terms of the single parameter sigma, which can be estimated from experimental data .