Each system was first minimized for 4000 steps with 500 kcal/mol/Å 2 positional restraints on the heavy atoms present in the protein-ligand complex, followed by another 4000 steps of minimization with 50 kcal/mol/Å 2 positional restraints only on the protein atoms. Next we performed MD simulations in the NVT ensemble to slowly heat the system and to release the restraints on the protein atoms using the following steps: i) 20 ps of simulation with 25 kcal/mol/Å 2 restraints at 10 K, ii) gradual heating of the sytem from 10 to 300 K for 40 ps with 5 kcal/mol/Å 2 restraints, iii) 20 ps of simulation with 5 kcal/mol/Å 2 restraints at 300 K, iv) 40 ps of simulation with 1 kcal/mol/Å 2 restraints, v) 40 ps of simulation with 0.1 kcal/mol/Å 2 restraints, and vi) 40 ps of simulation without any restraints. In a final phase of equilibration, we ran the system in the NPT ensemble using a Monte Carlo barostat for 5 ns to get the correct density at 1 atmospheric pressure.