For each system, we first used steepest descent to minimize the water for 5000 steps, followed by a 1 ns heating of the system to 300 K in the NVT ensemble using a Langevin thermostat and a timestep of 1 fs. This was followed by an NPT equilibration with the Berendsen barostat and a timestep of 1 fs, to allow the box density to relax. The nonbonded cutoff was 8 Å and the long-range interactions were calculated with Particle-mesh Ewald. We then reduced the position restraints of the solute from 100 kcal mol -1 Å-1 to 10 kcal mol -1 Å-1 . The 10 kcal mol -1 Å-1 backbone restraints were then relaxed for 1 ns before reducing them to 1 kcal mol -1 Å-1 and to 0.1 kcal mol -1 Å-1 over 1 ns, each. Finally, the system was relaxed without positional restraints for 1 ns before the final 50 ns production run, using a 2 fs timestep.