Protein folding is an important but challenging scientific problem and is currently the focus of numerous experimental, theoretical and computational studies. Whilst the driving forces underlying protein folding have been identified, the relative importance of these driving forces has not been established. In particular, the importance of the “hydrophobic effect” and the significance of water mediated interactions are still controversial. We have recently developed an approach to compute hydration free energies with quantitative accuracy and applied it to water molecules in protein cavities. The approach is based on inhomogeneous fluid solvation theory (IFST), a statistical mechanical method in which free energy changes are calculated as the sum of enthalpic and entropic contributions. Recent research has shown that converged enthalpy and entropy estimates can be derived from long timescale molecular dynamics simulations. IFST has proven to be useful in understanding hydration phenomena in a number of contexts but has not been applied to protein folding. In this context, free energy differences can be calculated by applying IFST analysis to simulations of folded and unfolded protein conformations. We calculate differences in the intramolecular protein interaction energy, intermolecular protein-water interaction energy, intermolecular water-water interaction energy, and two-particle solvent entropy. We do not estimate the entropy terms related to the protein degrees of freedom, which we assume will strongly favour the unfolded state. However, the signs and magnitudes of the other terms are informative. IFST is an ideal method to study free energy changes in protein folding, where traditional pathway methods such as free energy perturbation and thermodynamic integration are unfeasible due to the sizeable nature of the perturbations. The two major questions in protein folding are (1) how do proteins fold and (2) why do proteins fold. In this study, we address the second question. Thus, whilst the findings will not speak to the mechanisms involved in protein folding and cannot explain how proteins fold, they will elucidate the underlying thermodynamic driving forces and thus help to explain why proteins fold in computational simulations. The results will be of interest to both experimentalists and theoreticians in the field of protein structure.

Dissecting energetic and entropic contributions to protein folding

251st National Meeting (2016)

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