Toward the Computational Design of Artificial Metalloenzymes: From Protein–Ligand Docking to Multiscale Approaches

Abstract

The development of artificial enzymes aims at expanding the scope of biocatalysis. Over recent years, artificial metalloenzymes based on the insertion of homogeneous catalysts in biomolecules have received an increasing amount of attention. Rational or pseudorational design of these composites is a challenging task because of the complexity of the identification of efficient complementarities among the cofactor, the substrate, and the biological partner. Molecular modeling represents an interesting alternative to help in this task. However, little attention has been paid to this field so far. In this manuscript, we aim at reviewing our efforts in developing strategies efficient to computationally drive the design of artificial metalloenzymes. From protein−ligand dockings to multiscale approaches, we intend to demonstrate that modeling could be useful at the different steps of the design. This Perspective ultimately aims at providing computational chemists with illustration of the applications of their tools for artificial metalloenzymes and convincing enzyme designers of the capabilities, qualitative and quantitative, of computational methodologies.

Design of an enantioselective artificial metallo-hydratase enzyme containing an unnatural metal-binding amino acid

“…Protein–ligand docking was carried out following the procedure we optimized for artificial metalloenzymes. 56 In short, calculations were performed with the program GOLD and the ChemScore scoring function. 57 The covalent docking option was used with a junction between the Cβ position of residue 89 and the 5 position of the 2,2′-bipyridine.…”

Molecular Dynamics Simulation and Kinetic Study of Fluoride Binding to V21C/V66C Myoglobin with a Cytoglobin-like Disulfide Bond

“…This is especially the case for heme protein design, which has received much attention in the last few decades, and various approaches have been established for rational design, such as the introduction of non-heme metal ions and unnatural amino acids, and the use of heme mimics to act as an active site [1][2][3][4][5][6][7][8][9][10][11][12]. Importantly, computer modeling and molecular dynamics (MD) simulation play key roles in guiding the protein design [13][14][15][16][17][18]. For example, computer simulation was successfully applied to design a non-heme iron binding site in the heme pocket of myoglobin (Mb), which converted an O 2 carrier into a functional nitric oxide reductase [19].…”

Prediction of the interaction of metallic moieties with proteins: An update for protein‐ligand docking techniques

“…In the case of metallodrugs, this represents the nexus of a major computational challenge. Indeed, how to deal with the formation of coordination bond through the metal and a donor of an amino acid side chain is a very diffuse situation . When dealing with a metalloprotein and the possibility to interact with a coordination bond between the metal and an organic ligand (Scheme a), most of the programs nowadays available offer some solutions .…”