The importance of hydration for the kinetics and thermodynamics of proteinfolding: simplified lattice models

Background: Recent studies have proposed various sources for the origin of cooperativity in simplified protein folding models. Important contributions to cooperativity that have been discussed include backbone hydrogen bondin g, sidechain packing and hydrophobic interactions. Related work has also fo cused on which interactions are responsible for making the free energy of t he native structure a pronounced global minimum in the free energy landscap e. In addition, two-flavor bead models have been found to exhibit poor fold ing cooperativity and often lack unique native structures. We propose a sim ple multibody description of hydration with expectations that it might modi fy the free energy surface in such a way as to increase the cooperativity o f folding and improve the performance of two-flavor models. Results: We study the thermodynamics and kinetics of folding for designed 3 6-mer sequences on a cubic lattice using both our solvation model and the c orresponding model without solvation terms. Degeneracies of the native stat es are studied by enumerating the maximally compact states. The histogram M onte Carlo method is used to obtain folding temperatures, densities of stat es and heat capacity curves. Folding kinetics are examined by accumulating mean first-passage times versus temperature. Sequences in the proposed solv ation model are found to have more unique ground states, fold faster and fo ld with more cooperativity than sequences in the nonsolvation model. Conclusions: We find that the addition of a multibody description of solvat ion can improve the poor performance of two-flavor lattice models and provi de an additional source for more cooperative folding. Our results suggest t hat a better description of solvation will be important for future theoreti cal protein folding studies.