Enantioselective Binding of Propranolol and Analogues Thereof to Cellobiohydrolase Cel7A

Abstract

At the catalytic site for the hydrolysis of cellulose the enzyme cellobiohydrolase Cel7A binds the enantiomers of the adrenergic beta-blocker propranolol with different selectivity. Methyl-to-hydroxymethyl group modificationso f propranolol, which result in higher affinity andi mproveds electivity, were herein studied by 1 H, 1 Ha nd 1 H, 13 Cs calar spinspin coupling constants as well as utilizing the nuclearO verhauser effect( NOE) in conjunction with molecular dynamics simulations of the ligandsp er se, whichs howedt he presence of all-antiperiplanar conformations, except for the one containing av icinal oxygen-oxygen arrangementg overned by the gauche effect. For the ligand-protein complexes investigated by NMR spectroscopy using, inter alia, transferred NOESY and saturation-transfer difference( STD) NMR experiments the S-isomers were shown to bind with ah ighera ffin-ity and ac onformation similar to that preferred in solution, in contrastt ot he R-isomer.T he fact that the S-form of the propranolol enantiomer is pre-arrangedf or binding to the protein is also observed for ac rystals tructureo fd ihydroxy-(S)-propranolol and Cel7A presentedh erein.W hereas the binding of propranolol is entropyd riven, the complexation with the dihydroxya naloguei sa nticipated to be favored also by an enthalpic term, such as fori ts enantiomer, that is, dihydroxy-(R)-propranolol, because hydrogen-bond donation replacest he corresponding bondingf rom hydroxyl groups in glucosyl residues of the natural substrate. In addition to a favorable entropy component, albeit lesseri nm agnitude, this represents an effect of enthalpy-to-entropy compensation in ligand-protein interactions.

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

“…These conformations give a conformational penalty, which affects the GlideScore more than the Emodel scoring. The conformations of Cel7A/ 1 and Cel7A/ 2 in solution were recently studied by various nuclear magnetic resonance techniques, and the results concur with our results in the solid state 29 …”

“…The conformations of Cel7A/1 and Cel7A/2 in solution were recently studied by various nuclear magnetic resonance techniques, and the results concur with our results in the solid state. 29 The results from docking and scoring showed an unexpectedly good correlation with the experimental affinities, in particular the Emodel scoring function, considering that it was concluded in a recently reported assessment of docking programs and scoring functions (including Glide and GlideScore) that none of the programs or scoring functions made a useful prediction of ligand binding affinity. 30 Hence, the docking results' ability to distinguish between compounds close in affinity exceeded our expectations.…”

Anisotropic 1H STD‐NMR Spectroscopy: Exploration of Enantiomer‐Polypeptide Interactions in Chiral Oriented Environments

“…[27][28][29][30][31] Interestingly, this tool has also been employed for investigating polar solutes interacting with soft matters (as stationary phases used in HPLC) by 1 H high-resolution magic angle spinning (HRMAS) NMR at low speed, [32] as well as applied successfully to characterize enantiomers-macromolecule interactions in achiral isotropic liquids. [33][34][35][36] However, the STD-NMR approach has never been tested so far to investigate the case of chiral lyotropic liquid crystals, to the best of our knowledge.…”

Direct Evidence for Aligned Binding of Cellulase Enzymes to Cellulose Surfaces

“…The CBM-P peptide mimics the tyrosine motif within the binding surface of the CBM. Images were generated in Visual Molecular Dynamics (VMD) using PDB codes 6GRN for cellulase and 2MWK for the CBM.…”