Prior to the DA-QM-FMO calculations, all snapshots were treated with a restrained minimization procedure with the OPLS3e force field to alleviate steric clashes, following the protein preparation wizard protocol of Schrödinger's software suite. The heavy atoms of the protein were permitted to move up to 0.3 Å from their original position in the crystal structure, while the heavy atoms of the ligand and water molecules were restrained in position with a force of 1.0 kcal/mol/Å; hydrogen atoms were left unrestrained. The restraint weight was set to ensure that the binding poses of the ligands did not deviate far from their initial positions.