AbstractHerein, we present results from molecular dynamics (MD) simulations of the human butyrylcholinesterase (BuChE) enzyme in aqueous solution. Two configurations of the unbound form of BuChE differing in the presence or absence of a sodium ion inside the protein gorge were simulated for 10 and 5 ns, respectively. Besides complementing the structural information provided by X‐ray data, the MD simulations give insight into the structure of the native BuChE enzyme. For example, it is shown that: the nucleophilic Ser198 residue and the various binding subsites in the BuChE catalytic cavity are readily accessible from the exterior of the protein; the presence of the sodium ion dynamically explores two different binding sites in the gorge leading to the active site and stabilizes the productive conformation of the Glu325/His438/Ser198 catalytic triad; several long‐lived water bridges are fully integrated into the architecture of the active site; the positions of the residues at the rim o