Theoretical perspective on the structure and mechanism of cytochrome P450 enzymes.
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Catalysis↗
Biomedical subjects
Sason Shaik
Publications and source records attributed to Sason Shaik.
Computer-generated high-valent iron--oxo and manganese--oxo species with polyoxometalate ligands: how do they compare with the iron--oxo active species of heme enzymes?
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Algorithms↗
Valence bond calculations of hydrogen transfer reactions: a general predictive pattern derived from theory.
Hydrogen abstraction reactions of the type X(*) + H-H' --> X-H + H'(*) (X = F, Cl, Br, I) are studied by ab initio valence bond methods and the VB state correlation diagram (VBSCD) model. The reaction barriers and VB parameters of the VBSCD are computed by using the breathing orbital valence bond and valence bond configuration interaction methods. The combination of the VBSCD model and semiempirical VB theory leads to analytical expressions for the barriers and other VB quantities that match the ab initio VB calculations fairly well. The barriers are influenced by the endo- or exothermicity of the reaction, but the fundamental factor of the barrier is the average singlet-triplet gap of the bonds that are broken or formed in the reactions. Some further approximations lead to a simple formula that expresses the barrier for nonidentity and identity hydrogen abstraction reactions as a function of the bond strengths of reactants and products. The semiempirical expressions are shown to be useful not only for the model reactions that are studied in this work, but also for other nonidentity and identity hydrogen abstraction reactions that have been studied in previous articles.
Journal Article↗
External electric field will control the selectivity of enzymatic-like bond activations.
Controlling the selectivity of a chemical reaction is a Holy Grail in chemistry. This paper reports theoretical results of unprecedented effects induced by moderately strong electric fields on the selectivity of two competing nonpolar bond activation processes, C-H hydroxylation vs C=C epoxidation, promoted by an active species that is common to heme-enzymes and to metallo-organic catalysts. The molecular system by itself shows no selectivity whatsoever. However, the presence of an electric field induces absolute selectivity that can be controlled at will. Thus, the choice of the orientation and direction of the field vis-à-vis the molecular axes drives the reaction in the direction of complete C-H hydroxylation or complete C=C epoxidation.
Biomimetic Materials↗
One oxidant, many pathways: a theoretical perspective of monooxygenation mechanisms by cytochrome P450 enzymes.
Density functional theoretical studies of monooxygenation reactivity of the high-valent oxoiron(IV) porphyrin cation-radical compound of cytochrome P450, the so-called Compound I, and of its precursor, the ferric(III)-hydroperoxide species, are described. The degeneracy of the spin states of Compound I, its electron deficiency, and dense orbital manifold lead to two-state and multi-state reactivity scenarios and may thereby create reactivity patterns as though belonging to two or more different oxidants. Most of the controversies in the experimental data are reconciled using Compound I as the sole competent oxidant. Theory finds ferric(III)-hydroperoxide to be a very sluggish oxidant, noncompetitive with Compound I. If and when Compound I is absent, P450 oxidation will logically proceed by another form, but this has to be more reactive than ferric(III)-hydroperoxide. Theoretical studies are conducted to pinpoint such an oxidant for P450.
Cytochrome P-450 Enzyme System↗
A predictive pattern of computed barriers for C-h hydroxylation by compound I of cytochrome p450.
The communication presents DFT calculations of 10 different C-H hydroxylation barriers by the active species of the enzyme cytochrome P450. The work demonstrates the existence of an excellent barrier-bond energy correlation. The so-obtained equation of the straight line is demonstrated to be useful for predicting barriers of related C-H activation processes, as well as for assessing barrier heights within the protein environment. This facility is demonstrated be estimating the barrier of camphor hydroxylation by P450cam.
Alkanes↗
Active anionic zero-valent palladium catalysts: characterization by density functional calculations.
This works uses DFT (B3LYP/LACVP*(+)//B3LYP/LACVP* level) to ascertain the existence of the tricoordinate, anionic zero-valent palladium complexes that were postulated as the active species in the catalytic cycles of Pd-catalyzed Heck and cross-coupling reactions. The variety of complexes studied (1 and 2), include [Pd(PR(3))(2)X](-) species, in which R=H, Me, vinyl, and phenyl, and X=Cl, Br, I, AcO, and TFA, as well as bidentate complexes, [Pd[Ph(2)P(CH(2))(n)Ph(2)P]X](-), in which X=Cl, AcO and n=3-6. The study shows that these complexes exist as distinct minima in the gas phase as well as in THF. In addition, it provides geometric features and Pd--X(-) dissociation energies for all these complexes as well as some NMR and IR data, which show a clear distinction in these features between the tri- and dicoordinate Pd(0) species. An orbital interaction model and perturbation theory arguments account for the bonding mechanism and rationalize all the trends in the stability of the Pd--X bond. These trends include the effects of variation of X, R, and the length of the linker in the bidentate ligands.
Journal Article↗
Oxygen economy of cytochrome P450: what is the origin of the mixed functionality as a dehydrogenase-oxidase enzyme compared with its normal function?
The economy of dioxygen consumption by enzymes constitutes a fundamental problem in enzymatic chemistry (ref 1). Sometimes, the enzyme converts ALL the oxygen into water, without affecting the organic substrate, thereby acting as an "oxidase" (ref 1). Other times, the enzyme converts all the oxygen into water and causes desaturation in the substrate, thus exhibiting a mixed function as both "oxidase" and "dehydrogenase" (refs 2-5). The present paper describes density functional calculations demonstrating that the oxidase-dehydrogenase mixed activity occurs from the cationic intermediate species and requires electro-steric inhibition of the rebound process. Furthermore, the calculations reveal that the carbocation is formally nascent from an excited state of the active species of the enzyme (2Cpd I), in which the Fe=O moiety is singlet coupled as in the 1Deltag state of dioxygen! Thus, our results resolve an important mechanism and reveal the factors that underlie its observability.
Catalysis↗
The ground and excited states of polyenyl radicals C2n-1H2n + 1 (n = 2-13): a valence bond study.
The semiempirical valence bond (VB) method, VBDFT(s), is applied to the ground states and the covalent excited states of polyenyl radicals C2n - 1H2n + 1 (n = 2-13). The method uses a single scalable parameter with a value that carries over from the study of the covalent excited states of polyenes (W. Wu, D. Danovich, A. Shurki, S. Shaik, J. Phys. Chem. A, 2000, 104, 8744). Whenever comparison is possible, the VB excitation energies are found to be in good accord with sophisticated molecular orbital (MO)-based methods like CASPT2. The symmetry-adapted Rumer structures are used to discuss the state-symmetry and VB constitution of the ground and excited states, and the expansion to VB determinants is used to gain insight on spin density patterns. The theory helps to understand in a coherent and lucid manner the properties of polyenyl radicals, such as the makeup of the various states, their geometries and energies, and the distribution of the unpaired electrons (the neutral solitons).
Journal Article↗
Quantum mechanical/molecular mechanical investigation of the mechanism of C-H hydroxylation of camphor by cytochrome P450cam: theory supports a two-state rebound mechanism.
The stereospecific cytochrome P450-catalyzed hydroxylation of the C(5)-H((5-exo)) bond in camphor has been studied theoretically by a combined quantum mechanical/molecular mechanical (QM/MM) approach. Density functional theory is employed to treat the electronic structure of the active site (40-100 atoms), while the protein and solvent environment (ca. 24,000 atoms) is described by the CHARMM force field. The calculated energy profile of the hydrogen-abstraction oxygen-rebound mechanism indicates that the reaction takes place in two spin states (doublet and quartet), as has been suggested earlier on the basis of calculations on simpler models ("two-state reactivity"). While the reaction on the doublet potential energy surface is nonsynchronous, yet effectively concerted, the quartet pathway is truly stepwise, including formation of a distinct intermediate substrate radical and a hydroxo-iron complex. Comparative calculations in the gas phase demonstrate the effect of the protein environment on the geometry and relative stability of intermediates (in terms of spin states and redox electromers) through steric constraints and electronic polarization.
Camphor↗
Porphyrin traps its terminator! Concerted and stepwise porphyrin degradation mechanisms induced by heme-oxygenase and cytochrome p450.
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Animals↗
Radical clock substrates, their C-H hydroxylation mechanism by cytochrome P450, and other reactivity patterns: what does theory reveal about the clocks' behavior?
There is an ongoing and tantalizing controversy regarding the mechanism of a key process in nature, C-H hydroxylation, by the enzyme cytochrome P450 (Auclaire, K.; Hu, Z.; Little, D. M.; Ortiz de Montellano, P. R.; Groves, J. T. J. Am. Chem. Soc. 2002, 124, 6020-6027. Newcomb, M.; Aebisher, D.; Shen, R.; Esala, R.; Chandrasena, P.; Hollenberg, P. F.; Coon, M. J. J. Am. Chem. Soc. 2003, 125, 6064-6065). To definitely resolve this controversy, theory must first address the actual systems that have been used by experiment, and that generated the controversy. This is done in the present paper, which constitutes the first extensive theoretical study of such two experimental systems, trans-2-phenylmethyl-cyclopropane (1) and trans-2-phenyl-iso-propylcyclopropane (4). The theoretical study of these substrates reveals that the only low energy pathway for C-H hydroxylation is the two-state rebound mechanism described originally for methane hydroxylation (Ogliaro, F.; Harris, N.; Cohen, S.; Filatov, M.; de Visser, S. P.; Shaik, S. J. Am. Chem. Soc. 2000, 122, 8977-8989). The paper shows that the scenario of a two-state rebound mechanism accommodates much of the experimental data. The computational results provide a good match to experimental results concerning the very different extents of rearrangement for 1 (20-30%) vs 4 (virtually none), lead to product isotope effect for the reaction of 1, in the direction of the experimental result, and predict as well the observed metabolic switching from methyl to phenyl hydroxylation, which occurs upon deuteration of the methyl group. Furthermore, the study reveals that an intimate ion pair species involving an alkyl carbocation derived from 4 gives no rearranged products, again in accord with experiment. This coherent match between theory and experiment cannot be merely accidental; it comes close to being aproof that the actual mechanism of C-H hydroxylation involves the two-state reactivity revealed by theory. Analysis of the rearrangement modes of the carbocations derived from 1 and 4 excludes the participation of free carbocations during the hydroxylation of these substrates. Finally, the mechanistic significance of product isotope effect (different isotope effects for the rearranged and unrearranged alcohol products) is analyzed. It is shown to be a sensitive probe of two-state reactivity; the size of the intrinsic product isotope effect and its direction reveal the structural differences of the hydrogen abstraction transition states in the low-spin vs high-spin reaction manifolds.
Cyclopropanes↗
A practical valence bond method: a configuration interaction method approach with perturbation theoretic facility.
The previously developed valence bond configuration interaction (VBCI) method (Wu, W.; Song, L.; Cao, Z.; Zhang, Q.; Shaik, S., J. Phys. Chem. A, 2002, 105, 2721) that borrows the general CI philosophy of the MO theory, is further extended in this article, and its methodological features are improved, resulting in three accurate and cost-effective procedures: (a) the effect of quadruplet excitation is incorporated using the Davidson correction, such that the new procedure reduces size consistency problems, with due improvement in the quality of the computational results. (b) A cost-effective procedure, named VBCI(D, S), is introduced. It includes doubly excited structures for active electrons and singly excited structures for inactive pairs. The computational results of VBCI(D, S) match those of VBCISD with much less computational effort than VBCISD. (c) Finally, a second-order perturbation theory is utilized as a means of configuration selection, and lead to considerable reduction of the computational cost, with little or no loss in accuracy. Applications of the new procedures to bond energies and barriers of chemical reactions are presented and discussed.
Journal Article↗
How do aldehyde side products occur during alkene epoxidation by cytochrome P450? Theory reveals a state-specific multi-state scenario where the high-spin component leads to all side products.
A theoretical study of alkene epoxidation, by the high-valent iron-oxo species (Compound I) of cytochrome P450, reveals a multi-state scenario in which the different products are generated in a state specific manner. All the low-spin doublet state processes are effectively concerted epoxide producing pathways. By contrast, all the high-spin quartet processes are stepwise and either lead to epoxide that does not conserve the isomeric identity of the alkene (cis or trans), or/and to by-products such as suicidal complexes and aldehydes. The product/state inventory is the following: (a) The epoxide with conserved alkene stereochemistry is generated from the low-spin doublet states of Compound I in a nonsynchronous but effectively concerted pathways that involve carbon radical (with Fe(III) and Fe(IV)) and cationic intermediates. (b) The epoxide with scrambled alkene stereochemistry is obtained from the quartet high-spin radical intermediate (with Fe(IV)). (c) The suicidal complex, with a C-N bond between the alkene and the porphyrin, is obtained from the high-spin cationic state that possesses one electron in the sigma xy* orbital (the antibonding Fe-N orbital made from dxy and nitrogen sigma-hybrids). (d) The aldehyde by-product is obtained from the high-spin cationic state that possesses one electron in the sigma xy* orbital (the antibonding O-Fe-S orbital made from dz2 and the oxo and sulfur sigma-hybrids). Factors controlling the competition between these processes are discussed.
Alkenes↗
Mechanism of oxidation reactions catalyzed by cytochrome p450 enzymes.
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Cytochrome P-450 Enzyme System↗
Active species of horseradish peroxidase (HRP) and cytochrome P450: two electronic chameleons.
The active site of HRP Compound I (Cpd I) is modeled using hybrid density functional theory (UB3LYP). The effects of neighboring amino acids and of environmental polarity are included. The low-lying states have porphyrin radical cationic species (Por(*)(+)). However, since the Por(*)(+) species is a very good electron acceptor, other species, which can be either the ligand or side chain amino acid residues, may participate in electron donation to the Por(*)(+) moiety, thereby making Cpd I behave like a chemical chameleon. Thus, this behavior that was noted before for Cpd I of P450 is apparently much more wide ranging than initially appreciated. Since chemical chameleonic behavior property was found to be expressed not only in the properties of Cpd I itself, but also in its reactivity, the roots of this phenomenon are generalized. A comparative discussion of Cpd I species follows for the enzymes HRP, CcP, APX, CAT (catalase), and P450.
Binding Sites↗
How does product isotope effect prove the operation of a two-state "rebound" mechanism in C-H hydroxylation by cytochrome P450?
C-H hydroxylation is a fundamental process. In Nature it is catalyzed by the enzyme cytochrome P450, in a still-debated mechanism that poses a major intellectual challenge for both experiment and theory; currently, the opinions keep swaying between the original single-state rebound mechanism, a two-oxidant mechanism (where ferric peroxide participates as a second oxidant, in addition to the primary active species, the high-valent iron-oxo species), and two-state reactivity (TSR) mechanism (where two spin states are involved). Recent product isotope effect (PIE) measurements for the trans-2-phenyl-methyl cyclopropane probe (1), led Newcomb and co-workers (Newcomb, M.; Aebisher, D.; Shen, R.; Esala, R.; Chandrasena, P.; Hollenberg, P.; Coon, M. J. J. Am. Chem. Soc. 2003, 125, 6064-6065) to rule out TSR in favor of the two-oxidant scenario, since the direction of the PIE was at odds with the one predicted from calculations on methane hydroxylation. The present report describes a density functional theoretical study of C-H hydroxylation of the Newcomb probe, 1, leading to rearranged (3) and unrearranged (2) products. Our study shows that the reaction occurs via TSR in which the high-spin pathway gives dominant rearranged products, whereas the low-spin pathway favors unrearranged products. The calculated PIE(2/3) values based on TSR are found to be in excellent agreement with the experimental data of Newcomb and co-workers. This match between experiment and theory makes a strong case that the reaction occurs via TSR mechanism.
Cyclopropanes↗
Electrophilic aromatic chlorination and haloperoxidation of chloride catalyzed by polyfluorinated alcohols: a new manifestation of template catalysis.
We have demonstrated that a polyfluorinated alcohol, 2,2,2-trifluoroethanol, solvent enables haloperoxidase type activity and the oxychlorination of arenes (benzene and its alkylated derivatives) without a metal catalyst. The polyfluorinated alcohol has a dual function; it catalyzes electrophilic chlorination of less reactive arenes by several orders of magnitude and oxidation of chloride at lower H+ concentrations. DFT calculations show that a complementary charge template in the transition state explains the catalysis of the electrophilic chlorination.
Journal Article↗