Integrated Computational Study of the Cu-Catalyzed Hydration of Alkenes in Water Solvent and into the Context of an Artificial Metallohydratase

Abstract

Despite the increasing efforts in the last few years, the identification of efficient catalysts able to perform the enantioselective addition of water to double bonds has not been achieved yet. Natural hydratases represent an interesting pool of biocatalysts to generate chiral alcohols, but modifying their substrate scope remains an issue. The use of artificial metalloenzymes (ArMs) appears as a promising solution in this field. In the last few years, Roelfes and co-workers have been designing a variety of DNA-and protein-based ArMs able to carry out the copper-mediated addition of water to conjugated alkenes with promising enantioselective levels. Still, from a mechanistic point of view, the copper-mediated hydration reaction remains unclear and a matter of debate. This lack of information greatly hampers further designs and optimizations of the LmrR-based copper hydratases in terms of substrates and/or enantioselective profiles. In this study, we aim to provide a better understanding of the copper-catalyzed hydration of alkenes occurring both in water solvent and into the context of the LmrR protein as designed by Roelfes and coworkers. For that purpose, we make use of an integrated computational protocol that combines quantum mechanics (QM) (including small and large cluster models as well as ab initio molecular dynamics (AIMD)) and force-field approaches (including protein−ligand docking and classical molecular dynamics (MD) simulation). This integrative study sheds light on the general doubts around the copper-catalyzed hydration mechanism and also paves the way toward more conscious designs of ArMs able to efficiently catalyze the enantioselective addition of water to double bonds.

Molecular Modeling for Artificial Metalloenzyme Design and Optimization

“…Schematic representation of the modeling study to decode LmrR-Phen-Cu­(II) water mediated hydration mechanism . Top: The surface of the entire ArM is represented in blue with the catalytic site out and in ball and stick representation.…”

“…Combining protein−ligand dockings and MD simulations, we used the near-to-catalysis pregeometric criteria to select MD snapshots as starting point of large full-QM cluster calculations to simulate the enantiospecific hydration pathways. 52 This integrative approach showed that the origin of the enantioselectivity was related to a negatively charged residue D100 in the binding pocket, an amino acid identified experimentally as the major ee promoter (Figure 5).…”

Rationalizing the Decavanadate(V) and Oxidovanadium(IV) Binding to G-Actin and the Competition with Decaniobate(V) and ATP

“…The DFT level of theory and RESP model to assign the atomic charges were selected following the protocol proposed to derive AMBER and TIP3P force fields for molecular dynamics (MD). 27 …”

“…Point charges of the complete POMs were derived with the RESP (Restrained ElectroStatic Potential) model. The DFT level of theory and RESP model to assign the atomic charges were selected following the protocol proposed to derive AMBER and TIP3P force fields for molecular dynamics (MD) …”

Designer metalloenzymes for synthetic biology: Enzyme hybrids for catalysis

“…Nevertheless, many different reactions have been targeted by chemists looking to develop more sustainable catalysts that utilise water as a solvent, low temperatures and allow metal recycling (see Figure 1C-E for examples) [23][24][25][26][27]. ArMs have also begun to provide solutions for reactions where small molecule catalysts have not achieved the desired selectivity [28,29].…”