UBC Theses and Dissertations
Implicit solvent models and free energies of solvation in the context of protein folding Cumberworth, Alexander Michael
Given the wide and fundamental roles proteins play in cells, as well as their potential medical and industrial applications, a detailed understanding of the relationships between sequence, structure, dynamics, and function is of critical importance. Molecular models are required to solve this problem, as well as models of the associated conformational spaces. One of the most challenging aspects of modeling these vast ensembles is the computer power required to carry out the requisite simulations. Reduced solvent models, and particularly a class referred to as implicit solvent models, have been developed extensively; however, they make many assumptions and approximations that are likely to affect accuracy. Here, several implicit solvent models commonly used for protein modeling are evaluated by comparing the expected changes in free energies of solvation upon folding ΔGsolv derived from micro--ms simulations of fast folding proteins to those given by the implicit solvent models. In the majority of cases, there is a significant and substantial difference between the ΔGsolv values calculated from the two approaches, with the implicit solvent models excessively favouring the folded state over the unfolded state. This could only be remedied by selecting values for the model parameters -- the internal dielectric constant for the polar term and the surface tension coefficient for the apolar term -- that were system specific or physically unrealistic.
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