Schematic showing the path followed to calculate the free energy difference between the crystal structure (top left) and misfolded structure (bottom left) of the WW domain. The dashed arrow shows the overall free energy difference, indicating that the misfolded structure is actually much more stable than the folded structure in the simulations, and showing a crack in the reflection of the simulated system on physical reality. Solid arrows show the free energy differences for each of the individual steps used to break down the overall change to make it possible to calculate the difference between the two endpoints; following the path between the two structures clockwise is equivalent to going directly between them. The intermediates used in the free energy calculation procedure are, from left to right, constrained states (with springs fixing them to the reference structure), deactivated states (with all protein-protein interactions removed), and dummied states (with uniform van der Waals parameters and charges applied to all heavy atoms and to all hydrogens).