Unravelling novel synergies between organometallic and biological partners: a quantum mechanics/molecular mechanics study of an artificial metalloenzyme

Abstract

In recent years, the design of artificial metalloenzymes obtained by the insertion of homogeneous catalysts into biological macromolecules has become a major field of research. These hybrids, and the corresponding X-ray structures of several of them, are offering opportunities to better understand the synergy between organometallic and biological subsystems. In this work, we investigate the resting state and activation process of a hybrid inspired by an oxidative haemoenzyme but presenting an unexpected reactivity and structural features. An extensive series of quantum mechanics/molecular mechanics calculations show that the resting state and the activation processes of the novel enzyme differ from naturally occurring haemoenzymes in terms of the electronic state of the metal, participation of the first coordination sphere of the metal and the dynamic process. This study presents novel insights into the sensitivity of the association between organometallic and biological partners and illustrates the molecular challenge that represents the design of efficient enzymes based on this strategy.

Elucidation of Binding Site and Chiral Specificity of Oxidovanadium Drugs with Lysozyme through Theoretical Calculations

“…Another aspect is the full relaxation of the first coordination sphere of the metal during the binding. Even if major changes of this environment are rarely observed in the structures of metallodrugs bound to their targets, this aspect could be studied, as demonstrated in the literature, , through QM/MM refinement.…”

Molecular Modeling for Artificial Metalloenzyme Design and Optimization

“…The calculations showed that the unusual binding mode in the X-ray structure was linked to (1) the smaller size of salophen with respect to the natural substrate (the heme) and (2) the flexibility of the helix that contains the glutamate. Moreover, we could unambiguously associate the X-ray structure to an unprecedented resting state and identify the entire activation mechanism of the enzyme including cofactor–host induced motions …”

Validation and Applications of Protein–Ligand Docking Approaches Improved for Metalloligands with Multiple Vacant Sites

“…In particular, the possibility of multiple coordination and stabilization through secondary interactionshardly demonstrable with most of the experimental techniques (ESI-MS, CD, and UV–vis)can be substantiated by docking methods. A possible improvement of the bond distances and angles could be obtained through refinement of the metal binding sites predicted by docking through the quantum mechanics/molecular mechanics (QM/MM) method (see refs and ).…”

“…The background of the docking is thoroughly discussed in refs and and the historical development of the methods in refs – . Initially, the method was applied to the inert binding of small organic molecules, and only subsequently were the first attempts to simulate the interaction of metal-containing ligands made (Scheme a). , However, like for most force field-based approaches, dealing with metallo ligands is far from straightforward because the effect of the metal and the possibility that one or more coordination bonds are formed must be considered. Even if covalent docking methods are available for software such as GOLD , Autodock , CovalentDock , and Docktite , their applications to metal complexes have several limitations: for example, the formation of chemical bonds is forced a priori through energetic restraints and is generally limited to specific bond classes.…”