A two-step equilibration procedure is followed here. First, binding site waters were equilibrated using the AMBER MC/MD procedure 67 as implemented in AMBER18's pmemd.cuda engine . The system first underwent a short initial equilibration phase consisting of 10,000 steps of minimisation, followed by a 500 ps NVT phase, and then 5 ns of NPT. During this equilibration, protein backbone atoms and non-hydrogen ligand atoms were restrained using a 5 kcal/mol/Å 2 force constant. The system then underwent a 5 ns MC/MD with the same positional restraints with 25 000 MC attempts every 1 000 MD steps. This was followed by a further 10 ns of MC/MD water exchange with position restraints on the ligand removed. In all MC/MD simulations, the NVT ensemble was sampled and the MC swap region box was trimmed to ensure as many exchanges with binding site waters as possible.