Hydrogen Bonds and n → π* Interactions in the Acetylation of Propranolol Catalyzed by Candida antarctica Lipase B: A QTAIM Study

Abstract

Enzyme−substrate interactions play a crucial role in enzymatic catalysis. Quantum theory of atoms in molecules (QTAIM) calculations are extremely useful in computational studies of these interactions because they provide very detailed information about the strengths and types of molecular interactions. QTAIM also provides information about the intramolecular changes that occur in the catalytic reaction. Here, we analyze the enzyme−substrate interactions and the topological properties of the electron density in the enantioselective step of the acylation of (R,S)-propranolol, an aminoalcohol with therapeutic applications, catalyzed by Candida antarctica lipase B. Eight reaction paths (four for each enantiomer) are investigated and the energies, atomic charges, hydrogen bonds, and n → π* interactions of propranolol, the catalytic triad (composed of D187, H224, and S105), and the oxyanion hole are analyzed. It is found that D187 acts as an electron density reservoir for H224, and H224 acts as an electron density reservoir for the active site of the protein. It releases electron density when the tetrahedral intermediate is formed from the Michaelis complex and receives it when the enzyme−product complex is formed. Hydrogen bonds can be grouped into noncovalent and covalent hydrogen bonds. The latter are stronger and more important for the reaction than the former. We also found weak n → π* interactions, which are characterized by QTAIM and the natural bond orbital (NBO) analysis.

Intermolecular n→π* Interactions in Supramolecular Chemistry and Catalysis

“…Furthermore, through 13 C NMR titrations and DFT calculations, it was revealed that the catalyst can form complexes with substrates, thereby catalyzing the respective reactions (Figure 15c). Doerr and coworkers [26] set up a quantum theory of atoms in molecules (QTAIM) and natural bond orbital analysis to analyze the enzyme-substrate interactions in acylation of (R,S)propranolol catalyzed by Candida antarctica lipase B. The optimized tetrahedral intermediate structure of enzyme and propranolol enantiomers indicated n!π* interactions between the OH oxygen of propranolol and the carbonyl group of the acyl serine in the Michaelis complex (MCC), and between the OH oxygen of serine and the carbonyl group of the acylated propranolol in the enzyme product complex (EPC).…”