Prior to production runs, energy minimization and, for the protein and ligand leg of the cycle, a short 50 ps NVT simulation were performed. During these runs the solute heavy atoms were position restrained with a force constant of 1000 kJ/mol/nm 2 . Subsequently, 6 ns equilibrium simulations were performed in an NPT ensemble. The temperature was kept at 298 K with the velocity rescaling thermostat 57 with a time constant of 2 ps. 1 bar pressure was retained with the Parrinello-Rahman barrostat with a time constant of 5 ps. Electrostatic interactions were handled via Smooth Particle Mesh Ewald 59,60 with 1.1 nm real space cutoffs. Van der Waals interactions were switched off from 1.0 nm to 1.1 nm. Isotropic corrections for both energy and pressure due to long-range dispersion were applied. All bond lengths were constrained via the LINCS algorithm .