Skip to main content
SLU publication database (SLUpub)

Research article2023Peer reviewedOpen access

Chiral recognition mechanism of cellobiohydrolase Cel7A for ligands based on the β-blocker propranolol: The effect of explicit water molecules on binding and selectivities

Fagerstroem, Alexandra; Liljefors, Tommy; Sandgren, Mats; Isaksson, Roland; Stahlberg, Jerry; Berg, Ulf

Abstract

Proteins are useful chiral selectors. In order to understand the recognition mechanism and chiral discrimination, the binding of the (R)- and (S)-enantiomers of a series of designed amino alcohol inhibitors based on propranolol to cellobiohydrolase Cel7A (Trichoderma reesei) has been studied more closely. X-ray crystal structures were determined of the protein complex with the (R)- and (S)-enantiomers of the strongest binding propranolol analogue. The combination of the structural data, thermodynamic data from capillary electrophoresis and microcalorimetry experiments and computational modelling give a clearer insight into the origin of the enantioselectivity and its opposite thermodynamic signature. The new crystal structures were used in computational molecular flexible dockings of the propranolol analogues using the program Glide. The results indicated that several water molecules in the active site were essential for the docking of the (R)-enantiomers but not for the (S)-enantiomers. The results are discussed in relation to the enantiomeric discrimination of the enzyme. Both dissociation constants (Kd values) and thermodynamical data are included to show the effects of the structural modifications in the ligand on enthalpy and entropy in relation to the enantioselectivity.Propranolol and eight derivatives have been designed for the study of the chiral discrimination when binding to the enzyme Cel7A. Structural data, thermodynamic data from capillary electrophoresis and microcalorimetry experiments together with computational modelling indicate that eight water molecules (W1-W8) determine the structure, thermodynamics and the chiral selectivity.dagger image

Keywords

Cel7A; computational chemistry; enantioselectivity; inhibitor binding; propranolol; thermodynamics

Published in

Natural sciences
2023, Volume: 3, number: 3, article number: e20220050