We first demonstrate that AtomNet PoseRanker enriches pose quality for compounds docked to single conformations of their cognate receptors as well as non-cognate receptors in the crossdocked PDBbind v2019 data set compared to conventional approaches. Our results indicate that training on a cross-docked data set teaches AtomNet PoseRanker to recognize distinct poses as valid in different receptor conformations. AtomNet PoseRanker trained on FlexPDBbind v2019 achieved nearly the same enrichment, suggesting that computationally sampled conformational ensembles can augment experimental ensembles when the latter are not available. Finally, we examined how conformationally diverse ensembles affect enrichment of active compounds in a virtual screen of Abl kinase. Ensemble-based procedures generally outperformed those using a single conformation. Strikingly, however, we found that using a single conformation with a crossdocked trained AtomNet PoseRanker achieved nearly identical enrichment as that using an ensemble, suggesting that DL approaches can infer flexibility from the training set. C) The GluN2A NMDA receptor ligand-binding domain in complex with its cognate activating ligand L-glutamate (L-GLU, pdb ID 4nf8 (slate)) and antagonist 1-(phenanthrene-2carbonyl)piperazine-2,3-dicarboxylic acid (PPDA, pdb ID 4nf6 (grey)). The L-Glu occupied site requires dramatic structural changes to accommodate the larger antagonist. D) Mutations distal to the binding site (yellow) can shift the conformational equilibrium, thereby stabilizing non-binding substates or abrogating substates that are required for conformational selection. E) The compound imatinib in complex with Abl kinase (pdb ID 2hyy, slate). Imatinib binds Abl kinase in the inactive I2 state, which occupies a population of ~6% in WT Abl (pdb ID 6xrg, grey). A distal H415P mutation in Abl kinase, at a distance of 18Å from the active site, reduces affinity for the inhibitor imatinib five-fold. H415P destabilizes the I2 state, reducing its population to below detectable levels (pdb ID 2f4j, salmon). Note the A-loop in the open conformation.