Molecular dynamics. The systems 6W63, 7PHZ, 8P57 were studied in 500-ns unbiased MD simulations, using GROMACS 2019.2 and the Amber14SB force field . The TIP3P model was used for the water molecules, while the ligand was parameterized using the General AMBER Force Field (GAFF) with AM1-BCC charges . The protein was pre-processed using Schrodinger's Protein Preparation Wizard and the protonation state of residues in the active site was compared and confirmed with the output of the VirginiaTech H++ Web Server 55 . N-terminal acetyl and C-terminal amide capping groups were added to the 7PHZ and 8P57 structures. The protein and the ligand were then placed at the center of a 16 x 16 x 16 cubic nanometers box, and solvated with water and 0.15M NaCl. The systems were minimized with 50,000 steps of steepest descent, 50,000 steps of conjugate gradient, and then heated from 5K to 310K over the course of 5 ns, followed by a 1-ns equilibration stage in an NPT ensemble. During the annealing and NPT equilibration, 1000 kJ/mol restraints were applied on the C alpha atoms and on the ligand, along all three coordinates. The restraints were then released for the 500-ns unbiased simulation conducted with a timestep of 2fs, Parrinello-Rahman barostat, Velocity Rescale thermostat, and LINCS constraints on all bonds. Long-range electrostatics interactions were handled with Particle Mesh Ewald (PME) using 1.6 Å of grid spacing. The cutoff radius of van der Waals interaction and short-range electrostatics was set to 1.2 Å.