Fig. 4. Unbinding of an inhibitor from the N-terminal domain of Hsp90.

a Structural evolution along the dissociation pathway in Hsp90, showing protein surface in gray, inhibitor as van der Waals spheres, Asp93 and water molecules as sticks. The inhibitor is bound to the protein in a cleft of the protein surface via a hydrogen bond to Asp93. dcTMD calculations of b free energy ΔG(x) and, c (Gaussian-smoothed) friction Γ(x) together with the mean number of hydrogen bonds between inhibitor and water. Highlighted are the bound state 1, transition state and state with maximal friction 2, an additional state with increased friction 3 and the unbound state 4. Error bars of free energy and friction estimates are given in Supplementary Fig. 2. Fluctuations of Γ(x) for x ≳ 1 nm are due to noise. Color code as in Fig. 3.