The study of relationships between substrate structure and enzyme stereoselectivity was approached by means of a new molecular descriptor: the “differential Hybrid Molecular Interaction Field” (dH-MIF). The descriptor was conceived with the purpose of combining enthalpic and entropic information related to enzyme–enantiomer interactions. The dH-MIFs were developed based on experimental data previously published by the group of Karl Hult on the enantioselectivity of the W104A mutant of lipase B from Candida antarctica, which is endowed with an enlarged stereoselectivity pocket. Because of the increased conformational freedom of substrates, the entropic contribution to enantiodiscrimination is particularly relevant in kinetic resolution of alcohols catalyzed by this enzyme. By combining molecular dynamic simulations and GRID analysis the new dH-MIF descriptors proved to be able to extract both enthalpic and entropic information from models of the tetrahedral intermediates of enantiomers.
