Conventional myosin is representative of biomolecular motors in which the hydrolysis of Adenosine triphosphate (ATP) is coupled to large-scale structural transitions both in and remote from the active site. The mechanism that underlies such “mechanochemical coupling”, especially the causal relationship between the hydrolysis and the allosteric structural changes, has remained elusive despite extensive experimental and computational analyses. In this study, using combined quantum mechanical and molecular mechanical (QM/MM) simulations and different conformations of the myosin motor domain, we provide evidence to support that regulation of ATP hydrolysis activity is not limited to residues in the immediate environment of the γ phosphate. Specifically, we illustrate that efficient hydrolysis of ATP depends not only on the proper orientation of the lytic water but also the structural stability of several nearby residues, especially the Arg238-Glu459 salt-bridge (the numbering of residues follows the myosin II in Dictyostelium discoideum) and the water molecule that spans this salt-bridge and the lytic water. More importantly, by comparing the hydrolysis activity in two motor conformations with very similar active site (i.e., Switch-I and II) configurations, which distinguishes this work from our previous study, the results clearly indicate that the ability of these residues to make their crucial electrostatic stabilization relies on the configuration of residues in the nearby N-terminus of the relay helix and the “wedge loop”. Without the structural support from those motifs, residues in a closed active site in the post-rigor motor domain undergo subtle structural variations that lead to consistently higher calculated ATP hydrolysis barriers than in the pre-powerstroke state. In other words, starting from the post-rigor state, turning on the ATPase activity requires not only displacement of Switch II to close the active site but also structural transitions in the N-terminus of the relay helix and the “wedge loop”, which have been proposed previously to be ultimately coupled to the rotation of the converter subdomain 40 Å away.