Rationalization of a Streptavidin Based Enantioselective Artificial Suzukiase: An Integrative Computational Approach

• Published in: Chemistry : a European journal Vol. 30; no. 39; pp. e202401165 - n/a
• Main Authors: Tiessler‐Sala, Laura, Maréchal, Jean‐Didier, Lledós, Agustí
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 11-07-2024
• Subjects: Artificial metalloenzyme; Asymmetric Suzuki-Miyaura coupling; Biaryl; Biotin; Biotin - analogs & derivatives; Biotin - chemistry; Catalysis; Chemical reactions; Chemical synthesis; Computer applications; Couplings; Cross coupling; Density Functional Theory; Enantiomers; Integrative computational approach; Ligands; Metalloproteins - chemistry; Metalloproteins - metabolism; Molecular Docking Simulation; Molecular dynamics; Molecular Dynamics Simulation; Molecular modeling; Mutation; Stereoisomerism; Streptavidin; Streptavidin - chemistry; Streptavidin - metabolism; Substrates; Asymmetric Suzuki-Miyaura coupling; Integrative computational approach; Molecular modeling; Biaryl; Artificial metalloenzyme
• ISSN: 0947-6539; 1521-3765; 1521-3765
• DOI: 10.1002/chem.202401165

An Artificial Metalloenzyme (ArM) built employing the streptavidin‐biotin technology has been used for the enantioselective synthesis of binaphthyls by means of asymmetric Suzuki‐Miyaura cross‐coupling reactions. Despite its success, it remains a challenge to understand how the length of the biotin cofactors or the introduction of mutations to streptavidin leads the preferential synthesis of one atropisomer over the other. In this study, we apply an integrated computational modeling approach, including DFT calculations, protein‐ligand dockings and molecular dynamics to rationalize the impact of mutations and length of the biotion cofactor on the enantioselectivities of the biaryl product. The results unravel that the enantiomeric differences found experimentally can be rationalized by the disposition of the first intermediate, coming from the oxidative addition step, and the entrance of the second substrate. The work also showcases the difficulties facing to control the enantioselection when engineering ArM to catalyze enantioselective Suzuki‐Miyaura couplings and how the combination of DFT calculations, molecular dockings and MD simulations can be used to rationalize artificial metalloenzymes.
A computational modeling approach is applied to rationalize the impact of streptavidin mutations and length of the biotion cofactor on the enantioselective Suzuki‐Miyaura synthesis of binaphthyls by means of an Artificial Metalloenzyme built employing the streptavidin‐biotin technology. The integrative computational approach includes DFT calculations, protein‐ligand dockings and molecular dynamics simulations.