Secondary isotope effects for carbonyl addition reactions of methyl thioacetate, acetone and acetaldehyde have been calculated by ab initio quantum mechanical methods in an effort to interpret measured b-deuterium isotope effects on acetylcholinesterase-catalyzed hydrolysis of acetylthiocholine. The calculated b-deuterium isotope effect for equilibrium addition of methanol to methyl thioacetate is ^D3K_eq = 0.965, and the corresponding effect for addition of methoxide ion to methyl thioacetate wherein three waters are hydrogen bonded to the carbonyl oxyanion is ^D3K_eq = 1.086. Neither of these calculated isotope effects is as inverse as the experimental b-deuterium isotope effect for acetylcholinesterase-catalyzed hydrolysis of acetylthiocholine, ^D3k_E = 0.90±0.03. Structural comparisons show that the water-solvated methoxide adduct of methyl thioacetate is more expanded than is the neutral methanol addition adduct, and suggest that the degree to which the isotope effect is inverse (i.e. less than) is inversely correlated to the degree of expansion of the adduct. A similar correlation of a-deuterium and b-deuterium secondary isotope effects with the degree of expansion of the adducts is found for equilibrium additions of methanol and methoxide ion to acetaldehyde. These computational results suggest that the markedly inverse b-deuterium isotope effect for the acetylcholinesterase reaction arises from enzymic compression of the transition state.