Resumo

BARRERA VALDERRAMA, Daniel Iván; DOERR, Markus  e  DAZA ESPINOSA, Martha Cecilia. Rol of the near attack conformers during enantioselective acylation of (R,S)-propranolol catalysed by Candida antarctica lipase B. Rev. colomb. biotecnol [online]. 2018, vol.20, n.1, pp.16-30. ISSN 0123-3475.  https://doi.org/10.15446/rev.colomb.b¡ote.v20n1.73652.

Candida antarctica lipase B (CalB) has been used for chemo- and enantioselective acylation of racemic (R,S)-propranolol, with moderate enantioselectivity (£=63) for R-propranolol. The enantioselective step in this reaction is the transfer of an acyl group from the catalytic acylated serine to propranolol. The initial phase of this reaction involves the formation of Michaelis complexes, followed by the formation of near-attack complexes. The analysis of the near-attack complexes has in several cases permitted to explain the origin of the catalysis or to reproduce the catalytic effect. The aim of this study was improve the understanding of the role of the near-attack complexes for the enantioselectivity of the acylation of (R,S)-propranolol, catalyzed by CalB. To this purpose a detailed investigation of the Michaelis and near-attack complexes of the enantioselective step of the acylation of (R,S)-propranolol using QM/MM molecular dynamics was performed. Several simulations (each 2,5 ns) with different initial velocity distributions were performed. In total seven CalB-propranolol complexes were studied. The hydrogen bonds in the active site of CalB, which are relevant for the catalytic activity, are stable in all simulations. The lifetime of the Michaelis complexes is considerably shorter than the simulation time. Conclusions: The populations of the Michaelis and near-attack complexes depend on the initial velocity distribution in the molecular dynamics simulations. The experimentally observed moderate enantioselectivity may be partially attributed to the high population of near-attack conformations of S-propranolol.

Palavras-chave : enzymology; adrenergic beta-receptor blockers; catalytic domain; computer simulation.

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