Unveiling the structure of a novel artificial heme‐enzyme with peroxidase‐like activity: A theoretical investigation

Abstract

Fe(III)-Mimochrome VI (MC6) is a recently reported artificial heme-peptide conjugate system with a high peroxidase-like activity. By design, its structure features a five-coordinated Fe(III)-deuteroporphyrin active site, embedded in a compact α-helix-heme-α-helix "sandwich" motif. Up to now, no detailed MC6 structural characterization is available. In this work we propose a theoretical investigation based on molecular dynamics (MD) simulations and hybrid quantum mechanics/molecular mechanics (QM/MM) optimizations, aimed to shed light on several Fe(III)-MC6 structural features and to validate the de novo designed fold. Key structural elements were analyzed to achieve indirect insight relevant to understand Fe(III)-MC6 catalytic performances in solution. Extensive MD simulations showed a partial stability of the "sandwich" fold in water solution. The smaller peptide chain bonded to the heme revealed a high conformational freedom, which promoted the exposition of the heme distal side to the solvent. Regarding the accessibility of water molecules, even in Fe(III)-MC6 "closed" structure the heme cavity appeared hydrated, suggesting an easy accessibility by exogenous ligands. Fe(III)-MC6 structure in both high and low spin states was then further characterized through hybrid QM/MM optimizations. In particular, an accurate description of the active site structure was obtained, allowing a direct comparison of Fe(III)-MC6 coordination environment with that observed in the Horseradish Peroxidase crystal structures. Our results suggest a structural similarity between Fe(III)-MC6 and the natural enzyme. This study supports the interpretation of data from experimental Fe(III)-MC6 structural and functional characterization and the rational design of new artificial mimics with improved catalytic performances.

Mimochrome, a metalloporphyrin‐based catalytic Swiss knife†

“…Indeed, the spectroscopic characterization of the isolated Fe MC6* C-I derivative confirmed this hypothesis [263]. As a further support, theoretical analysis identified the Arg10(D)-Glu2(TD) as the weaker among the four ion pairs occurring in MC6 analogues [255].…”

“…UV-Vis analysis suggested that ferric MC6 could be in the high-spin (S = 5/2) state; however, resonance Raman spectroscopy suggested that it could be best described as an admixed state (S = 3/2, 5/2) [249], as already observed in Cyt c and in artificial peroxidases [253,254]. The generation of this electronic state was recently supported by a QM-MM (quantum mechanics/molecular mechanics) analysis [255]. Electrochemical analysis was performed on FeMC6 either when adsorbed on electrode surface or freely diffusing in solution ( Table 1).…”

Water-Mediated Excited State Proton Transfer of Pyranine–Acetate in Aqueous Solution: Vibrational Fingerprints from Ab Initio Molecular Dynamics

“…The implicit and structureless solvent surrounding the explicit sphere was accounted for in the energy potential and completed the hybrid explicit/implicit solvation model. More specifically, nonperiodic boundary conditions accounted for the interactions of both electrostatic and dispersion–repulsion nature between the explicit molecular system and the implicit bulk solvent. − The solvent molecules were explicitly represented by the TIP3P water model, while the implicit bulk solvent was represented by the polarizable continuum model in its conductor-like version. , The explicit system itself is treated at different levels of theory according to the hybrid QM/MM ONIOM extrapolative method employing an electronic embedding scheme. − In particular, the pyranine–water–acetate system is described by DFT and TD-DFT in the ground and excited electronic state, respectively, by adopting the global hybrid B3LYP functional and the 6-31g­(d,p) basis set. The obtained energy potential ruled the AIMD simulations in both the ground and the first singlet excited state.…”

Iron(III) Complexes for Highly Efficient and Sustainable Ketalization of Glycerol: A Combined Experimental and Theoretical Study

“…The 6-31+G­(d,p) basis set was adopted for C, H, and O, whereas the Fe atom was described by the LANL2DZ basis set and the associate effective core potential, which was demonstrated to be a suitable choice to describe the reactivity of metal centers. − …”