MOLECULAR MODELING OF THE ENANTIOSELECTIVITY IN LIPASE-CATALYZED TRANSESTERIFICATION REACTIONS

Two strategies based on the use of subsets for calculating the enantio selectivity in lipase-catalyzed transesterifications using the CHARMM force field were investigated. Molecular dynamics was used in our sear ch for low energy conformations. Molecular mechanics was used for refi ning these low energy conformations. A tetrahedral intermediate with a rigid central part was used for mimicking the transition state. The e nergy differences between the transition states of the diastereomeric enzyme-substrate complexes were calculated. The way of defining the su bsets was based on two fundamentally different strategies. The first s trategy used predefined parts of the enzyme and the substrate as subse ts. The second approach formed energy-based subsets, varying in size w ith the substrates studied. The selection of residues to be included i n these energy-based subsets was based on the energy of the interactio n between the specific residue or water molecule and the transition st ate. The reaction studied was the kinetic resolution of secondary alco hols in transesterifications using the Candida antarctica lipase B as chiral biocatalyst. The secondary alcohols used in the study were 2-bu tanol, 3-methyl-2- butanol, and 3,3-dimethyl-2-butanol.