The system was subject to minimization, thermalization and equilibration procedures, where harmonic restraints on the protein and ligands were progressively removed, except for those on the backbone of the last 5 residues of each subunit (residues 236 to 240 according to the PDB numbering) which were kept at 1 kcal/(mol Å2 ). This was followed by a 1000 ns production MD in the NPT ensemble at 310 K and 1 atm. The temperature was controlled by a Langevin thermostat, with a coupling coefficient of 1 ps -1 . The pressure was controlled by a Langevin piston barostat, with an oscillation period of 200 fs and a damping timescale of 100 fs.