The lipase from Pseudomonas cepacia represents
a widely applied catalyst for highly enantioselective resolution
of chiral secondary alcohols. While its stereopreference
is determined predominantly by the substrate structure,
stereoselectivity depends on atomic details of interactions
between substrate and lipase. Thirty secondary alcohols
with published E values using P. cepacia lipase
in hydrolysis or esterification reactions were selected,
and models of their octanoic acid esters were docked to
the open conformation of P. cepacia lipase. The
two enantiomers of 27 substrates bound preferentially in
either of two binding modes: the fast-reacting enantiomer
in a productive mode and the slow-reacting enantiomer in
a nonproductive mode. Nonproductive mode of fast-reacting
enantiomers was prohibited by repulsive interactions. For
the slow-reacting enantiomers in the productive binding
mode, the substrate pushes the active site histidine away
from its proper orientation, and the distance d(HNε
− Oalc) between the histidine
side chain and the alcohol oxygen increases. d(HNε
− Oalc) was correlated to experimentally
observed enantioselectivity: in substrates for which P.
cepacia lipase has high enantioselectivity (E
> 100), d(HNε −
Oalc) is >2.2 Å for slow-reacting
enantiomers, thus preventing efficient catalysis of this
enantiomer. In substrates of low enantioselectivity (E
< 20), the distance d(HNε
− Oalc) is less than 2.0 Å,
and slow- and fast-reacting enantiomers are catalyzed at
similar rates. For substrates of medium enantioselectivity
(20 < E < 100), d(HNε
− Oalc) is around 2.1 Å.
This simple model can be applied to predict enantioselectivity
of P. cepacia lipase toward a broad range of secondary
alcohols.