Details

Autor(en) / Beteiligte

• Valderrama, Daniel I.Barrera
• Daza, Martha C.
• Doerr, Markus

Titel

Finite-temperature effect in the O-acylation of (R,S)-propranolol catalyzed by Candida antarctica lipase B

Ist Teil von

• Journal of molecular graphics & modelling, 2021-09, Vol.107, p.107951-107951, Article 107951

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2021

Quelle

Access via ScienceDirect (Elsevier)

Beschreibungen/Notizen

• CalB is a triacylglycerol hydrolase (E.C.3.1.1.3) used in the O-acylation of the beta-adrenergic blocking agent (R,S)-propranolol. The catalytic mechanism involves two steps: enzyme acylation and enzyme deacylation. The enantioselectivity of the O-acylation of (R,S)-propranolol originates from the second step, where the acyl-enzyme transfers the acyl group to the racemic substrate. This step occurs via an initial Michaelis complex (MCC) and a tetrahedral intermediate (TI-2). To gain more insight into the molecular basis of this reaction, we performed an exhaustive conformational sampling along the reaction coordinate of the enantioselective step of the reaction (MCC→TI-2→EPC) applying a QM/MM MD protocol (SCC-DFTB/CHARMM) in combination with umbrella sampling and the weighted histogram analysis method. To identify finite temperature effects we compare the PMF and the potential energy pathway. It is found that the effect of the finite temperature in this reaction is a destabilization of the tetrahedral intermediate and an increase of the barrier height of its formation. This increase is higher for the S-enantiomer. [Display omitted] •The free energy of the CalB-catalyzed acylation of (R/S)-propranolol was calculated.•The tetrahedral intermediate (TI) is not an analogue of the transition state (TS).•Finite-temperature effects increase the energy of the TS and of the TI.