Computational study of the enantioselectivity of the O-acetylation of (R,S)-propranolol catalyzed by Candida antarctica lipase B

Candida antarctica lipase B (CalB) displays moderate enantioselectivity when it catalyzes the acetylation of (R,S)-propranolol, favoring the faster transformation of the R-propranolol. With the aim to better understand the enantioselectivity of this reaction, we have performed a molecular dynamics (MD) study of the enzyme substrate complexes. Reactive enzyme substrate complexes were identified for both enantiomers of propranolol, which differ in their temporal stability and in their ability to reach the corresponding transition states (TS). Reactive complexes of R-propranolol present a better ability to be transformed by CalB than those of S-propranolol. This allows us to explain the enantioselectivity. Analysis of the enzyme–substrate interactions suggests that the CH-π interactions between the naphthyl rings of propranolol and the residues of the CalB binding pocket may play an important role in stabilizing the transition states involved in the transformation of the R-propranolol. The residues Ile189, Ala282 and Leu278 were identified as key residues for the enantioselectivity of CalB.