Placement prediction. Due to the intrinsic instability of water molecules distal from the protein surface, comparisons were focused on the hydration sites present in the first hydration shell of the ligand binding site. The first hydration shell around ligands was defined using a cutoff of 5 Å 111 from any ligand heavy atoms using the refined PDBbind dataset (v2018) . Ligands with serious steric clashes with the protein (< 2 Å distance between heavy atoms) were ignored. Additionally, hydration sites identified as trapped (i.e., unable to exchange with the bulk solvent) were excluded from the analysis due to known convergence issue found in MD simulations . To identify them, bulk solvent accessibility was determined using MSMS with the default probe radius (1.5 Å), except for fabp4 to allow characterizing its enclosed pocket (1.0 Å). For hsp90α, the tightly bound hydration site W1 (Fig. ) was manually set as bulk-accessible. The quality of the predictions with respect to MD simulations was assessed by defining two metrics, the True Positive Rate (TPR, sensitivity, or recall), and the Positive Predictive Value (PPV, precision), calculated as following: