Butyrylcholinesterase is a key enzyme that catalyzes the hydrolysis of the neurotransmitter acetylcholine and shows an increased activity in patients suffering from Alzheimer’s disease (AD), making this enzyme a primary target in treating AD. Central to this problem, and to similar scenarios involving biomolecular recognition, is our understanding of the nature of the protein-ligand complex. The butyrylcholinesterase enzyme was studied via all-atom, explicit solvent, ensemble molecular dynamics simulations sans inhibitor and in the presence of three dialkyl phenyl phosphate inhibitors of known potency to a cumulative sampling of over 40 μs. Following relaxation of these ensembles to conformational equilibria, binding modes for each inhibitor were identified. While classical models, which assume significant reduction in both protein and ligand conformational entropies, continue to be favored in contemporary studies, our observations contradict those assumptions: bound ligands occupy many conformational states, thereby stabilizing the complex, while also promoting protein flexibility.