We have used molecular dynamics simulations to analyze the nucleotide site of myosin and its interaction with ATP and a catalytic water. Simulations used the Dictyostelium myosin ADP•VO4 x-ray crystal structure. This structure is widely hypothesized to be an analog of the hydrolysis transition state intermediate for an in-line water attack on the γ-phosphate position. The trigonal bi-pyramidal VO4 moiety was replaced by PO3 covalently bound to ADP and a water molecule oxygen. Surprisingly, the MD simulation indicated that the x-ray structure was not capable of controlling the position of the modeled attacking water as required for hydrolysis. Instead the water molecule rattled around a catalytic pocket formed by the γ-phosphate of ATP, elements of switch 1, switch 2, and the salt-bridge between R238 and E459. The salt-bridge has been postulated to serve to help stabilize the closed conformation of switch 2. The simulated double alanine R238A/E459A mutation eliminated this salt-bridge. There was little resulting change in the conformation of switch 2 (0.55A r.m.s. deviation, Cα-Cα, a.a. D454-L495) and the crucial hydrogen bond distance between the backbone amide of G457 and the γ-phosphate oxygen of ATP increased from 1.9A to only 2.0A in the mutated structure. However, the modeled catalytic water rapidly escaped from the catalytic pocket in the mutated myosin. Thus the simulations suggest that the closed-switch 2 structure is stabilized by a number of interactions in addition to the salt-bridge. The function of the salt-bridge is to serve as a lid to sequester water in the catalytic pocket.