An ab initio molecular orbital study of the first step of the catalytic mechanism of thymidylate synthase: The Michael addition of sulfur and oxygen nucleophiles

Ab initio molecular orbital calculations are used to study the Michael additions of sulfur and oxygen anionic nucleophiles to acrolein. The energetic and structural results of these calculations provide insight into the formation of the covalent enzyme-substrate complex of thymidylate synthase with dUMP, as well as the stereospecificity of Michael additions of heteroanionic nucleophiles. In addition, we discuss the interesting effect that substituents of the nucleophile (hydrogen vs methyl) have on the energy of reaction.