The Importance of Hydration for the Kinetics and Thermodynamics of Protein Folding: Simpli ed Lattice Models

Background: Recent studies have proposed various sources for the origin of cooperativity in simpliied protein folding models. Important contributions to cooperativity that have been discussed include backbone hydrogen bonding, side-chain packing, and hydrophobic interactions. Related work has also focused on what interactions are responsible for making the free energy of the native structure a pronounced global minimum in the free energy landscape. In addition, two-avor bead models have been found to exhibit poor folding cooperativity, and often lack unique native structures. We propose a simple multi-body description of hydration with expectations that it might modify the free energy surface in such a way as to increase the cooperativity of folding and improve the performance of two-avor models. Results: We study the thermodynamics and kinetics of folding for designed 36-mer sequences on a cubic lattice using both our solvation model and the corresponding model without solvation terms. Degeneracies of the native states are studied by enumerating the maximally compact states. The histogram Monte Carlo method is used to obtain folding temperatures, densities of states, and heat capacity curves. Folding kinetics are examined by accumulating mean rst-passage times versus temperature. Sequences in the proposed solvation model are found to have more unique ground states, fold faster, and fold with more cooperativity than sequences in the non-solvation model. Conclusion: We nd that the addition of a multi-body description of solvation can improve the poor performance of two-avor lattice models and provide an additional source for more cooperative folding. Our results suggest that a better description of solvation will be important for future theoretical protein folding studies.