Abstract
Solvation forces are crucial determinants in the equilibrium between the folded and unfolded state of proteins. Particularly interesting are the solvent forces of denaturing solvent mixtures on folded and misfolded states of proteins involved in neurodegeneration. The C-terminal globular domain of the ovine prion protein (1UW3) and its analogue H2H3 in the α-rich and β-rich conformation were used as model structures to study the solvation forces in 4 M aqueous urea using molecular dynamics. The model structures display very different secondary structures and solvent exposures. Most protein atoms favor interactions with urea over interactions with water. The force difference between protein-urea and protein-water interactions correlates with hydrophobicity; i.e., urea interacts preferentially with hydrophobic atoms, in agreement with results from solvent transfer experiments. Solvent Shannon entropy maps illustrate the mobility gradient of the urea-water mixture from the first solvation shell to the bulk. Single urea molecules replace water in the first solvation shell preferably at locations of relatively high solvent entropy.