Abstract A combined quantum chemical (PM3) and molecular mechanical (OPLS) study of the formation of the tetrahedral intermediate in the active site of acetylcholinesterase enzyme is presented. The influence of the protein environment on the reaction flow was investigated. It is shown that there are strong hydrogen bonds between the elements of the catalytic triad (Ser200-His440-Glu327) in the free enzyme. This fact, together with the unique form of the electrostatic potential in the active site of the enzyme, favour the activation of the serine residue for the subsequent attack of substrate. The interaction of the substrate with the “oxyanion hole” of the enzyme was demonstrated to lower the barrier height of the tetrahedral intermediate formation and to stabilize it substantially. The inhibition of the enzyme by the phospho-compound P(F)(O)(NH 2)(CH 3) was also investigated. The origin of the enzyme catalysis is discussed. The electrostatic interactions were concluded to be the principal cause of enzyme power.