Compound I in horseradish peroxidase enzyme: Magnetic state assessment by quadratric configuration interaction calculations

Zazza, Costantino; Sanna, Nico; Tatoli, Simone; Aschi, Massimiliano; Palma, Amedeo

doi:10.1002/qua.22267

Cited by 3 publications

(1 citation statement)

References 37 publications

(18 reference statements)

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“…In particular, C c P Cpd I has a protein radical (on Trp 191 ), while HRP and APX have a heme-based radical. Extensive computational studies using density functional theory, quantum mechanics/molecular mechanics and molecular dynamics studies have been performed on the various stages of the catalytic cycle of peroxidases and particularly on Cpd I [ 44 , 45 , 46 , 47 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 ]. These studies ( Scheme 1 ) confirmed Cpd I as a triradical species with three unpaired electrons, whereby two of those are on the metal (in the π* xz and π* yz orbitals), while the third radical is non-metal based [ 53 , 57 , 61 ].…”

Section: Introductionmentioning

confidence: 99%

How Does Replacement of the Axial Histidine Ligand in Cytochrome c Peroxidase by Nδ-Methyl Histidine Affect Its Properties and Functions? A Computational Study

Lee

Mubarak

Green

et al. 2020

IJMS

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Heme peroxidases have important functions in nature related to the detoxification of H2O2. They generally undergo a catalytic cycle where, in the first stage, the iron(III)–heme–H2O2 complex is converted into an iron(IV)–oxo–heme cation radical species called Compound I. Cytochrome c peroxidase Compound I has a unique electronic configuration among heme enzymes where a metal-based biradical is coupled to a protein radical on a nearby Trp residue. Recent work using the engineered Nδ-methyl histidine-ligated cytochrome c peroxidase highlighted changes in spectroscopic and catalytic properties upon axial ligand substitution. To understand the axial ligand effect on structure and reactivity of peroxidases and their axially Nδ-methyl histidine engineered forms, we did a computational study. We created active site cluster models of various sizes as mimics of horseradish peroxidase and cytochrome c peroxidase Compound I. Subsequently, we performed density functional theory studies on the structure and reactivity of these complexes with a model substrate (styrene). Thus, the work shows that the Nδ-methyl histidine group has little effect on the electronic configuration and structure of Compound I and little changes in bond lengths and the same orbital occupation is obtained. However, the Nδ-methyl histidine modification impacts electron transfer processes due to a change in the reduction potential and thereby influences reactivity patterns for oxygen atom transfer. As such, the substitution of the axial histidine by Nδ-methyl histidine in peroxidases slows down oxygen atom transfer to substrates and makes Compound I a weaker oxidant. These studies are in line with experimental work on Nδ-methyl histidine-ligated cytochrome c peroxidases and highlight how the hydrogen bonding network in the second coordination sphere has a major impact on the function and properties of the enzyme.

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Section: Introductionmentioning

confidence: 99%

How Does Replacement of the Axial Histidine Ligand in Cytochrome c Peroxidase by Nδ-Methyl Histidine Affect Its Properties and Functions? A Computational Study

Lee

Mubarak

Green

et al. 2020

IJMS

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Computational Study on Compound I Redox-Active Species in Horseradish Peroxydase Enzyme: Conformational Fluctuations and Solvation Effects

et al. 2010

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Molecular dynamics simulations for the compound I species in horseradish peroxidase were carried out over a nanoseconds time-scale. Results indicate that the supramolecular assembly composed of compound I in interaction with highly conserved distal residues (His42 and Arg38) exists in two well-defined conformations basically differing in the local position of the distal histidine (i.e., His42). Furthermore, we observe the presence of a biological channel in the distal side of the heme cavity, between Arg38 and Pro139 residues, that represents a direct link connecting the compound I (CpdI) species to bulk molecules. Our investigation supports the idea that when CpdI is formed, the biological machinery relaxes the local electrostatic forces, opening a structural channel through which an exchange of water molecules with the bulk solvent takes place without any significant kinetic barrier. Interestingly, we also show that the combined effect of enzyme and solvent, modulated by thermal fluctuations, affects the order and the energy difference between the lowest doublet and quartet magnetic states of the CpdI-His42-Arg38 complex. Consequently, when passing from the gas phase to the biological environment, the doublet spin state becomes slightly more stable than the higher spin multiplicity state. The distribution of the perturbed low-lying states energy variation, induced by surrounding fluctuations, yields results rather close to that obtained by other state of the art quantum-mechanics/molecular mechanics calculations, and still in line with previous polarizable continuum calculations.

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1.3 Modelling Radicals and Their Reactivities

Derat¹,

Braı̈da²

2021

Free Radicals: Fundamentals and Applications in Organic Synthesis 1

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In this chapter, the application of computational quantum mechanical methods to the understanding of radical reactions is introduced. For radical reactions, access to electronic configurations through quantum chemical calculations allows rationalization of unusual reactivities. Using the valence bond approach, the nature of bonding in three-electron bonds can be characterized by large resonance interactions. Similarly, some simple reactions that are commonly believed to be radical-free, such as [3 + 2] cycloadditions, are in fact governed by a high-lying biradical intermediate that helps to stabilize the transition state. More complex radical and enzymatic reactions can also be modelled, as illustrated by the example of horseradish peroxidase. These case studies show that computational analysis can complement experimental investigations and fill in the blanks to enable a more complete understanding of radical reactions.

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Compound I in horseradish peroxidase enzyme: Magnetic state assessment by quadratric configuration interaction calculations

Cited by 3 publications

References 37 publications

How Does Replacement of the Axial Histidine Ligand in Cytochrome c Peroxidase by Nδ-Methyl Histidine Affect Its Properties and Functions? A Computational Study

How Does Replacement of the Axial Histidine Ligand in Cytochrome c Peroxidase by Nδ-Methyl Histidine Affect Its Properties and Functions? A Computational Study

Computational Study on Compound I Redox-Active Species in Horseradish Peroxydase Enzyme: Conformational Fluctuations and Solvation Effects

1.3 Modelling Radicals and Their Reactivities

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