Computer-aided molecular modeling of the enantioselectivity of Pseudomonascepacia lipase toward gamma- and delta-lactones

Computer-aided molecular modeling was performed to investigate the experime ntally determined enantioselectivities of Pseudomonas cepacia Lipase (PCL) toward various saturated gamma- and delta-lactones. Experimental data indic ated that PCL preferentially hydrolyzes the (R)-enantiomers of both types o f substrates. Interactions between the non-polar aliphatic alkyl chain of t he (S)-enantiomers and the polar side chain of residue Y29 were identified to mediate enantioselectivity. Upon binding, the tyrosine was displaced, th us initiating a cascade of local geometry changes which led to the breakdow n of the essential H-bond network at the active site H286. The lactone ring of the (S)-delta-enantiomers further added to this process, since it was f orced into an unfavorable position by repulsion from Y29, directly affectin g the position of H286. In contrast, the respective (R)-enantiomers fit wit hout distorting side chains essential for catalysis in the binding pocket o f PCL. In delta-lactones, the stereocenter was located close to the imidazo le ring of H286, suggesting a more intense interaction with H286 as compare d to gamma-lactones. The length of the aliphatic chain adjacent to the ster eocenter also affected the enantiopreference toward hydrolysis of delta-lac tones, while for gamma-lactones, the enantioselectivity did not significant ly change with increasing alkyl chain length. In the cases of (S)-delta-oct a- and (S)-delta-nonalactone, two alternative possible binding modes were e xamined, indicating that the respective substrate resolutions led to poor e nantioselectivity as compared to the longer-chain delta-lactone substrates. (C) 2000 Elsevier Science B.V. All rights reserved.