P450 Enzymes: Their Structure, Reactivity, and Selectivity—Modeled by QM/MM Calculations

Shaik, Sason; Cohen, Shimrit; Wang, Yong; Chen, Hui; Kumar, Devesh; Thiel, Walter

doi:10.1021/cr900121s

Cited by 970 publications

(1,274 citation statements)

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“…The His and Tyr+Arg complexes had a +1 net charge, whereas the other three models were neutral. This protonated compound II state (formally Fe IV -OH -) has been suggested in the reaction mechanism of many haem oxidases, although the current consensus is that it is only involved in the reaction mechanisms when the axial ligand is Cys (the intermediate between the hydrogen-atom transfer and the rebound steps of cytochrome P450) [70,71].…”

Section: Protonated Compound II Models With Different Axial Ligandsmentioning

confidence: 99%

How are hydrogen bonds modified by metal binding?

Husberg

Ryde

2013

J Biol Inorg Chem

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How are hydrogen bonds modified by metal binding?Husberg, Charlotte; Ryde, Ulf General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.• Users may download and print one copy of any publication from the public portal for the purpose of private study or research.• You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal Take down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. AbstractWe have used density-functional theory calculations to investigate how the hydrogenbond strength is modified when a ligand is bound to a metal, using over 60 model systems involving six metals and eight ligands frequently encountered in metalloproteins. We study how the hydrogen-bond geometry and energy vary with the nature of metal, the oxidation state, the coordination number, the ligand involved in the hydrogen bond, other first-sphere ligands, and different hydrogen-bond probe molecules. The results show that in general, the hydrogen-bond strength is increased for neutral ligands and decreased for negatively charged ligands. The size of the effect is mainly determined by the net charge of the metal complex and all effects are typically decreased when the model is solvated. In water solution, the hydrogen-bond strength can increase by up to 37 kJ/mol for neutral ligands, and that of negatively charged ligands can both increase (for complexes with a negative net charge) or decrease (for positively charged complexes). If the net charge of the complex does not change, there is normally little difference between different metals or different types of complexes. The only exception is observed for sulphur-containing ligands (Met and Cys) and if the ligand is redox active (e.g. high-valent Fe-O complexes).Key Words: hydrogen bonds, metalloproteins, quantum-mechanical calculations, densityfunctional theory, dispersion correction, solvation. 2 IntroductionHydrogen bonds play an important role in all types of biochemical systems, strongly affecting catalysis, ligand binding, and enzyme function, for example [1]. They have been thoroughly studied by a variety of experimental and theoretical methods [2,3,4,5,6,7,8,9,10,11,12,13,14,15] so that the strengths of the common hydrogen bonds in biological systems are accurately known.However, it is well-known that metal sites affect the properties of bound ligands. For example, the pK a value of water in aqueous metal complexes is reduced from 15.7 for bulk water, to 12.8 for Ca 2+ and to 2.2 for Fe 3+ [16]. Therefore, it is also likely that metal ions also change the strength and structure of hydrogen bonds inv...

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Section: Protonated Compound II Models With Different Axial Ligandsmentioning

confidence: 99%

How are hydrogen bonds modified by metal binding?

Husberg

Ryde

2013

J Biol Inorg Chem

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“…complexes increase with increasing electron donation from the axial ligand. Their results have been extended to correlate the strong oxidizing power of the thiolate-ligated P450 enzyme to the strong electron donation from the axial thiolate ligand 31 .…”

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confidence: 99%

The biology and chemistry of high-valent iron–oxo and iron–nitrido complexes

2012

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selective functionalization of unactivated c-H bonds and ammonia production are extremely important industrial processes. a range of metalloenyzmes achieve these challenging tasks in biology by activating dioxygen and dinitrogen using cheap and abundant transition metals, such as iron, copper and manganese. High-valent iron-oxo and -nitrido complexes act as active intermediates in many of these processes. the generation of well-described model compounds can provide vital insights into the mechanism of such enzymatic reactions. advances in the chemistry of model high-valent iron-oxo and -nitrido systems can be related to our understanding of the biological systems.H igh-valent oxoiron(IV) and formally oxoiron(V) species have been spectroscopically identified as active intermediates in the catalytic cycles of a number of enzymatic systems 1-10 . Haem and non-haem proteins use these reactive intermediates to couple the activation of dioxygen to the oxidation of their substrates. In most cases, an oxygen atom is inserted into an unactivated C-H bond of the substrate; for example, in hydroxylation reactions [1][2][3][4][5][6][7][8][9][10] . However, many other reactions, including halogenation, desaturation, cyclization, epoxidation and decarboxylation, are also known to involve oxoiron species 1,3 . Superoxidized iron complexes with (valence) isoelectronic imido and nitrido ligands, as well as 'surface nitrides' , have also been implicated as key intermediates in the nitrogen atom transfer reactions 11 , the biological synthesis of ammonia by the nitrogenase enzyme 12-16 and the industrial Haber-Bosch process 17 .The generation of well-described model compounds can provide vital insights into the mechanism of such enzymatic reactions. Consequently, considerable effort has been made by synthetic chemists to prepare viable models for the putative reaction intermediates in the catalytic cycles of O 2 and N 2 activating enzymes. In this review, we provide an overview of all high-valent oxoiron and nitridoiron species that have been either identified or proposed as reactive intermediates in biology. Subsequently, we summarize some of the recent advances in bioinorganic chemistry that have led to the identification and isolation of iron complexes in unusually high formal oxidation states, containing iron-oxygen or iron-nitrogen multiple bonds. The spectroscopic characterization and the reactivity studies of these model complexes provide vital insights into the mechanism that nature uses to induce the reductive cleavage of dioxygen or dinitrogen in carrying out a number of important biochemical oxidative transformations. Moreover, the comparative review of the electronic structures of the isoelectronic oxoiron and nitridoiron functionalities reveals that the Fe-N bonds are intrinsically more covalent than the Fe-O bonds.

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“…Many techniques have been put forward to predict chemo-and regioselectivity, including traditional quantitative structure-activity relationship (QSAR) (9, 10) as well as three-dimensional QSAR models (10,11), construction of pharmacophore models for individual isoforms (12), substrate docking approaches using either crystal structures or homology models of the relevant enzyme (13), ab initio or density functional theory (DFT) calculations of reaction barriers and/or electronic properties (14), and rule-based methods (15). It is likely that a combination of methods will be required in general; hybrid quantum mechanical-molecular mechanics (QM/MM) methods, which allow modeling of specific effects of the protein on reactivity, have advanced to the stage where they can potentially make an important contribution (16).…”

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Understanding the determinants of selectivity in drug metabolism through modeling of dextromethorphan oxidation by cytochrome P450

Oláh

Mulholland

Harvey

2011

Proc. Natl. Acad. Sci. U.S.A.

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Cytochrome P450 enzymes play key roles in the metabolism of the majority of drugs. Improved models for prediction of likely metabolites will contribute to drug development. In this work, two possible metabolic routes (aromatic carbon oxidation and O-demethylation) of dextromethorphan are compared using molecular dynamics (MD) simulations and density functional theory (DFT). The DFT results on a small active site model suggest that both reactions might occur competitively. Docking and MD studies of dextromethorphan in the active site of P450 2D6 show that the dextromethorphan is located close to heme oxygen in a geometry apparently consistent with competitive metabolism. In contrast, calculations of the reaction path in a large protein model [using a hybrid quantum mechanical-molecular mechanics (QM/MM) method] show a very strong preference for O-demethylation, in accordance with experimental results. The aromatic carbon oxidation reaction is predicted to have a high activation energy, due to the active site preventing formation of a favorable transition-state structure. Hence, the QM/MM calculations demonstrate a crucial role of many active site residues in determining reactivity of dextromethorphan in P450 2D6. Beyond substrate binding orientation and reactivity of Compound I, successful metabolite predictions must take into account the detailed mechanism of oxidation in the protein. These results demonstrate the potential of QM/MM methods to investigate specificity in drug metabolism.C ytochrome P450 enzymes (P450s) form one of the most powerful defense mechanisms of living organisms: They protect against xenobiotics via an oxidative pathway, which in most instances leads to a less harmful and more soluble product with faster excretion. The same mechanism is involved in the metabolism of most drugs and alters the pharmacological activity of many drugs. As a consequence, P450-mediated transformations of drug candidates are of crucial importance in the pharmaceutical industry. The roles of P450s are manifold. Oxidation by P450s can lead to toxic products, but, on the other hand, local activation of, e.g., anticancer prodrugs by P450s to lethal intracellular toxins at the site of the tumor is an important strategy (1). Drug compounds can induce P450 expression but can also inhibit them in various ways (2-4). The metabolic clearance of most drugs depends on P450s, and they have been implicated in a large number of drug-drug interactions (5, 6), which can result in fatalities (7,8). Interactions of drug candidates with P450s must be taken into account during the drug discovery process if the expensive and time-consuming development of active compounds with hidden toxic effects is to be avoided.It is increasingly recognized that methods capable of predicting P450 oxidative activity for a given substrate, and also the predominant site(s) of metabolism, could contribute significantly to drug development. There are many aspects to this problem, including isoform selectivity (i.e., which P450 isoform will contribute mos...

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P450 Enzymes: Their Structure, Reactivity, and Selectivity—Modeled by QM/MM Calculations

Cited by 970 publications

References 405 publications

How are hydrogen bonds modified by metal binding?

How are hydrogen bonds modified by metal binding?

The biology and chemistry of high-valent iron–oxo and iron–nitrido complexes

Understanding the determinants of selectivity in drug metabolism through modeling of dextromethorphan oxidation by cytochrome P450

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