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Sason Shaik

Publications and source records attributed to Sason Shaik.

At least 19 recordsLinked to original sources
PubMed2006

The effect of heme environment on the hydrogen abstraction reaction of camphor in P450cam catalysis: a QM/MM study.

The discrepancies between the published QM/MM studies (Schöneboom, J. C.; Cohen, S.; Lin, H.; Shaik, S.; Thiel, W. J. Am. Chem. Soc. 2004, 126, 4017; Guallar, V.; Friesner, R. A. J. Am. Chem. Soc. 2004, 126, 8501) on H-abstraction of camphor in P450cam have largely been resolved. The crystallographic water molecule 903 situated near the oxo atom of Compound I acts as a catalyst for H-abstraction, lowering the barrier by about 4 kcal/mol. Spin density at the A-propionate side chain of heme can occur in the case of incomplete screening but has no major effect on the computed barrier.

Camphor↗
PubMed2006

A combined kinetic-quantum mechanical model for assessment of catalytic cycles: application to cross-coupling and Heck reactions.

The efficiency of catalytic cycles is measured by their turnover frequency (TOF). The degree of TOF control determines which states contribute most to the rate of the cycle, and thus indicates the steps that have the highest impact on the cycle. A kinetic model developed by Christiansen (Christiansen, J. A. Adv. Catal. 1953, 5, 311) for catalytic cycles is implemented here in a form that utilizes state energies. This enables one to assess the efficiency of quantum mechanically computed catalytic cycles like the palladium-catalyzed cross-coupling and Heck reactions, to test alternative hypotheses, and to make some predictions. This implementation can also account for effects such as Sabatier's volcano curve for heterogeneous catalysis. The model leads to a dependence of the TOF for any cycle on the "corrected" energy span quantity, deltaE, whose precise expression depends on the location of the summit and trough of the cycle in the step sequence of the cycle. Thus, knowing the highest energy transition state, the most abundant reaction intermediate, and the reaction energy enables one to make quick predictions about relative efficiency of cycles. At the same time, the degree of TOF control determines which states contribute most to the rate of reaction, and thus indicates the values to be included in the calculation of the energetic span and the steps that may be tinkered with to improve the cycle.

Journal Article↗
PubMed2006

Barriers of hydrogen abstraction vs halogen exchange: an experimental manifestation of charge-shift bonding.

This paper shows that the differences between the barriers of the halogen exchange reactions, in the H + XH systems, and the hydrogen abstraction reactions, in the X + HX systems (X = F, Cl, Br), measure the covalent-ionic resonance energies of the corresponding X-H bonds. These processes are investigated using CCSD(T) calculations as well as the breathing-orbital valence bond (BOVB) method. Thus, the VB analysis shows that (i) at the level of covalent structures the barriers are the same for the two series and (ii) the higher barriers for halogen exchange processes originate solely from the less efficient mixing of the ionic structures into the respective covalent structures. The barrier differences, in the HXH vs XHX series, which decrease as X is varied from F to I, can be estimated as one-quarter of the covalent-ionic resonance energy of the H-X bond. The largest difference (22 kcal/mol) is calculated for X = F in accord with the finding that the H-F bond possesses the largest covalent-ionic resonance energy, 87 kcal/mol, which constitutes the major part of the bonding energy. The H-F bond belongs to the class of "charge-shift" bonds (Shaik, S.; Danovich, D.; Silvi, B.; Lauvergnat, D. L.; Hiberty, P. C. Chem. Eur. J. 2005, 21, 6358), which are all typified by dominant covalent-ionic resonance energies. Since the barrier difference between the two series is an experimental measure of the resonance energy quantity, in the particular case of X = F, the unusually high barrier for the fluorine exchange reaction emerges as an experimental manifestation of charge-shift bonding.

Journal Article↗
PubMed2006

A single transition state serves two mechanisms. The branching ratio for CH2O*- + CH3Cl on improved potential energy surfaces.

The reaction of formaldehyde radical anion with methyl chloride, CH2O*- + CH3Cl, is an example in which a single transition state leads to two products: substitution at carbon (Sub(C), CH3CH2O* + Cl-) and electron transfer (ET, CH2O + CH3* + Cl-). The branching ratio for this reaction has been studied by ab initio molecular dynamics (AIMD). The energies of transition states and intermediates were computed at a variety of levels of theory and compared to accurate energetics calculated by the G3 and CBS-QB3 methods. A bond additivity correction has been constructed to improve the Hartree-Fock potential energy surface (BAC-UHF). A satisfactory balance between good energetics and affordable AIMD calculations can be achieved with BH&HLYP/6-31G(d) and BAC-UHF/6-31G(d) calculations. Approximately 200 ab initio classical trajectories were calculated for each level of theory with initial conditions sampled from a thermal distribution at 298 K at the transition state. Three types of trajectories were distinguished: trajectories that go directly to ET product, trajectories that go to Sub(C) product, and trajectories that initially go into the Sub(C) valley and then dissociate to ET products. The BH&HLYP/6-31G(d) calculations overestimate the number of nonreactive and direct ET trajectories because the transition state is too early. For the BH&HLYP and BAC-UHF methods, about one-third of the trajectories that initially go into the Sub(C) valley dissociate to ET products, compared to just over half with UHF/6-31G(d) in the earlier study. This difference can be attributed to a better value for the calculated energy release from the initial transition state and to an improved Sub(C) --> ET barrier height with the BH&HLYP and BAC-UHF methods.

Journal Article↗
PubMed2006

In silico design of a mutant of cytochrome P450 containing selenocysteine.

A mutant of P450(cam), in which the cysteine ligand was replaced by selenocysteine, was designed theoretically using hybrid QM/MM (quantum mechanical/molecular mechanical) calculations. The calculations of the active species, Se-CpdI (selenocysteine-Compound I), of the mutant enzyme indicate that Se-Cpd I will be formed faster than the wild-type species and be consumed more slowly in C-H hydroxylation. As such, our calculations suggest that Se-Cpd I can be observed unlike the elusive species of the wild-type enzyme (Denisov, I. G.; Makris, T. M.; Sligar, S. G.; Schlichting, I. Chem. Rev. 2005, 105, 2253-2277). Spectral features of Se-Cpd I were calculated and may assist such eventual characterization. The observation of Se-Cpd I will resolve the major puzzle in the catalytic cycle of a key enzyme in nature.

Amino Acid Substitution↗
PubMed2006

Kinetic isotope effect is a sensitive probe of spin state reactivity in C-H hydroxylation of N,N-dimethylaniline by cytochrome P450.

This paper presents DFT calculations of C-H hydroxylation of N,N-dimethylaniline by Compound I (Cpd I) of cytochrome P450. The reaction involves two processes nascent from the two spin states of Cpd I, the low-spin (LS) and high-spin (HS) states. The calculations demonstrate that the kinetic isotope effects (KIEs) of the two processes are very different, and only KIELS fits the experimental datum. As such, KIE can be a sensitive probe of spin state reactivity.

Aniline Compounds↗
PubMed2006

Gauging the relative oxidative powers of compound I, ferric-hydroperoxide, and the ferric-hydrogen peroxide species of cytochrome P450 toward C-H hydroxylation of a radical clock substrate.

Density functional calculations were performed in response to the controversies regarding the identity of the oxidant species in cytochrome P450. The calculations were used to gauge the relative C-H hydroxylation reactivity of three potential oxidant species of the enzyme, the high-valent oxo-iron species Compound I (Cpd I), the ferric hydroperoxide Compound 0 (Cpd 0), and the ferric-hydrogen peroxide complex Fe(H(2)O(2)). The results for the hydroxylation of a radical probe substrate, 1, show the following trends: (a) Cpd I is the most reactive species; in its presence the other two reagents will be silent. (b) In the absence of Cpd I, substrate oxidation by Cpd 0 and Fe(H(2)O(2)) will take place via a stepwise mechanism that involves initial O-O homolysis followed by H-abstraction from 1. (c) Cpd 0 will undergo mostly porphyrin hydroxylation and only approximately 15% of substrate oxidation producing mostly the rearranged alcohol, 3 (Scheme 2). (d) Fe(H(2)O(2)) will generate mostly free hydrogen peroxide (uncoupling). A small fraction will perform substrate oxidation and lead mostly to 3. Reactivity probes for these reagents are kinetic isotope effect (KIE) and the product ratio of unrearranged to rearranged alcohols, [2/3]. Thus, for substrate oxidation by Cpd 0 or Fe(H(2)O(2)) KIE will be small, approximately 2, while Cpd I will have large KIE values. Typically both Cpd 0 and Fe(H(2)O(2)) will lead to a [2/3] ratio < 1, while Cpd I will lead to ratios > 1. In addition, the product isotope effect (KIE(2)/KIE(3) not equal 1) is expected from the reactivity of Cpd I.

Catalysis↗
PubMed2005

The high-valent iron-oxo species of polyoxometalate, if it can be made, will be a highly potent catalyst for C-H hydroxylation and double-bond epoxidation.

This study uses density functional theory (DFT) calculations to explore the reactivity of the putative high-valent iron-oxo reagent of the iron-substituted polyoxometalate (POM-FeO4-), derived from the Keggin species, PW12O40(3-). It is shown that POM-FeO4- is in principle capable of C-H hydroxylation and C=C epoxidation and that it should be a powerful oxidant, even more so than the Compound I species of cytochrome P450. The calculations indicate that in a solvent, the barriers, and especially those for epoxidation, become sufficiently small that one may expect an extremely fast reaction. An experimental investigation (by R.N. and A.M.K.) shows, however, that the formation of POM-FeO4- using the oxygen donor, F5PhI-O, leads to a persistent adduct, POM-FeO-I-PhF5(4-), which does not decompose to POM-FeO4- + F5Ph-I at the working temperature and exhibits sluggish reactivity, in accord with previous experimental results (Hill, C. L.; Brown, R. B., Jr. J. Am. Chem. Soc. 1986, 108, 536 and Mansuy, D.; Bartoli, J.-F.; Battioni, P.; Lyon, D. K.; Finke, R. G. J. Am. Chem. Soc. 1991, 113, 7222). Subsequent calculations indeed reveal that the gas-phase binding energy of F5PhI to POM-FeO4- is high (ca. 20 kcal/mol) compared to the corresponding binding energy of propene (ca. 2-3 kcal/mol). As such, the POM-FeO-I-PhF5(4-) complex is expected to be persistent toward the displacement of F5PhI by a substrate like propene, leading thereby to sluggish oxidative reactivity. According to theory, overcoming this technical difficulty may turn out to be very rewarding. The question is, can POM-FeO4- be made?

Journal Article↗
PubMed2005

Charge-shift bonding--a class of electron-pair bonds that emerges from valence bond theory and is supported by the electron localization function approach.

This paper deals with a central paradigm of chemistry, the electron-pair bond. Valence bond (VB) theory and electron-localization function (ELF) calculations of 21 single bonds demonstrate that along the two classical bond families of covalent and ionic bonds, there exists a class of charge-shift bonds (CS bonds) in which the fluctuation of the electron pair density plays a dominant role. In VB theory, CS bonding manifests by way of a large covalent-ionic resonance energy, RE(CS), and in ELF by a depleted basin population with large variances (fluctuations). CS bonding is shown to be a fundamental mechanism that is necessary to satisfy the equilibrium condition, namely the virial ratio of the kinetic and potential energy contributions to the bond energy. The paper defines the atomic propensity and territory for CS bonding: Atoms (fragments) that are prone to CS bonding are compact electronegative and/or lone-pair-rich species. As such, the territory of CS bonding transcends considerations of static charge distribution, and involves: a) homopolar bonds of heteroatoms with zero static ionicity, b) heteropolar sigma and pi bonds of the electronegative and/or electron-pair-rich elements among themselves and to other atoms (e.g., the higher metalloids, Si, Ge, Sn, etc), c) all hypercoordinate molecules. Several experimental manifestations of charge-shift bonding are discussed, such as depleted bonding density, the rarity of ionic chemistry of silicon in condensed phases, and the high barriers of halogen-transfer reactions as compared to hydrogen-transfers.

Journal Article↗
PubMed2005

Principal active species of horseradish peroxidase, compound I: a hybrid quantum mechanical/molecular mechanical study.

The active species, Compound I, of horseradish peroxidase (HRP) has been investigated by quantum mechanical/molecular mechanical (QM/MM) calculations using 10 different QM regions. In accord with experimental data, the lowest doublet and quartet states are found to be virtually degenerate, with two unpaired electrons on the FeO moiety and one localized on the porphyrin in an a(2u)-dominant orbital with a minor, but nonnegligible, a(1u) component. The proximal ligand appears to be imidazole rather than imidazolate. The hydrogen-bonding network around the FeO moiety (i.e., Arg38 and His42) has significant influence on the axial bonds and the spin density distribution in the FeO moiety. Including this network in the QM region was found to be essential for reproducing the experimental Mössbauer parameters. The protein environment shapes most of the subtle features of Compound I of HRP.

Horseradish Peroxidase↗
PubMed2005

Two states and two more in the mechanisms of hydroxylation and epoxidation by cytochrome P450.

Past studies have shown that oxidation reactions by P450 Compound I (Cpd I) can be described by two competing quartet and doublet spin states, which possess three unpaired electrons, hence tri-radicals. One electron excitation from the delta orbital to sigma* xy generates two states that possess five unpaired electrons, so-called penta-radicals, in sextet and quartet situations, and which were shown by theory to lie only approximately 12-14 kcal/mol higher in energy than the tri-radical ground states (ref 7). The present study focuses on the C-H hydroxylation and C=C epoxidation of propene by these penta-radical states. It is shown that the initial energy differences, between the penta-radical and tri-radical states, diminish along the reaction pathway, due to the favorable and cumulative exchange stabilization of the more open-shell species. Furthermore, theory suggests that hydrogen bonding to the thiolate ligand, and general polarity of the environment, reduce these gaps further, thereby making the penta-radical states accessible to ground-state reactivity. The interconversion between the tri-radical and penta-radical states along the reaction coordinate will depend on the dynamics of spin-flips and energy barriers between the states. Especially interesting should be the region of the reaction intermediates; for both epoxidation and hydroxylation, this region is typified by a dense manifold of spin states and electromeric states (that differ by the oxidation state of iron), such that the total reactivity would be expected to reflect the interplay of these states, giving rise to multistate reactivity.

Alkenes↗
PubMed2005

Theory favors a stepwise mechanism of porphyrin degradation by a ferric hydroperoxide model of the active species of heme oxygenase.

The report uses density functional theory to address the mechanism of heme degradation by the enzyme heme oxygenase (HO) using a model ferric hydroperoxide complex. HO is known to trap heme molecules and degrade them to maintain iron homeostasis in the biosystem. The degradation is initiated by complexation of the heme, then formation of the iron-hydroperoxo species, which subsequently oxidizes the meso position of the porphyrin by hydroxylation, thereby enabling eventually the cleavage of the porphyrin ring. Kinetic isotope effect studies indicate that the mechanism is assisted by general acid catalysis, via a chain of water molecules, and that all the events occur in concert. However, previous theoretical treatments indicated that the concerted mechanism has a high barrier, much higher than an alternative mechanism that is initiated by O-O bond homolysis of iron-hydroperoxide. The present contribution studies the stepwise and concerted acid-catalyzed mechanisms using H(3)O(+)(H(2)O)(n)(), n = 0-2. The effect of the acid strength is tested using the H(4)N(+)(H(2)O)(2) cluster and a fully protonated ferric hydroperoxide. All the calculations show that a stepwise mechanism that involves proton relay and O-O homolysis, in the rate-determining step, has a much lower barrier (>10 kcal/mol) than the corresponding fully concerted mechanism. The best fit of the calculated solvent kinetic isotope effect, to the experimental data, is obtained for the H(3)O(+)(H(2)O)(2) cluster. The calculated alpha-deuterium secondary kinetic isotope effect is inverse (0.95-0.98), but much less so than the experimental value (0.7). Possible reasons for this quantitative difference are discussed. Some probes are suggested that may enable experiment to distinguish the stepwise from the concerted mechanism.

Biomimetic Materials↗
PubMed2005

Theoretical investigation of C--H hydroxylation by (N4Py)Fe(IV)=O(2+): an oxidant more powerful than P450?

DFT calculations of C-H hydroxylation by a synthetic nonheme oxoiron(IV) oxidant supported by a neutral pentadentate N5 ligand show that this reagent is intrinsically more reactive than compound I of P450. This nonheme iron oxidant is predicted to exhibit stereoselective reactions, strong solvent effect, and involve multistate reactivity with spin-state crossing.

Cytochrome P-450 Enzyme System↗
PubMed2005

Sulfoxidation mechanisms catalyzed by cytochrome P450 and horseradish peroxidase models: spin selection induced by the ligand.

The sulfoxidation of dimethyl sulfide (DMS), by two different heme-type enzyme models (without the protein), namely, horseradish peroxidase (HRP) and cytochrome P450 (P450), was studied using density functional theory. The models differ from each other by the axial ligand of the iron, which is imidazole in the case of HRP and thiolate in the case of P450. The computational results reveal a concerted oxygen atom transfer to sulfur, with spin-state selection dependent upon the identity of the proximal ligand. In the case of thiolate, the mechanism prefers the high-spin quartet pathway; whereas in the case of imidazole, the mechanism involves two-state reactivity (TSR), with competing quartet and doublet spin states. Furthermore, with thiolate the high-spin transition state, (4)TS(P450), has an upright conformation with a large Fe-O-S(DMS) angle of 147 degrees , whereas the low-spin species, (2)TS(P450), has a small angle and its Fe-O moiety makes an O-N(Por) bond with one of the nitrogen atoms of the porphine macrocycle. By contrast, when the proximal ligand is imidazole, both transition states possess a bent Fe-O bond and an O-N(Por) bond. These spin-state selection patterns obey simple orbital-selection rules, which are manifestations of the electronic nature of the ligand, i.e., the electron-releasing effect of the thiolate vis-a-vis the electron-withdrawal effect of imidazole. Other possible reactivity expressions of the spin-selection patterns are discussed [Dowers, T. S., Rock, D. A., Rock, D. A., Jones, J. P. (2004) J. Am. Chem. Soc. 126, 8868-8869]. Theory shows that intrinsically, HRP should be as reactive as P450 toward sulfoxidation.

Armoracia↗
PubMed2005

Multistate reactivity in styrene epoxidation by compound I of cytochrome p450: mechanisms of products and side products formation.

Density functional theoretical calculations are used to elucidate the epoxidation mechanism of styrene with a cytochrome P450 model Compound I, and the formation of side products. The reaction features multistate reactivity (MSR) with different spin states (doublet and quartet) and different electromeric situations having carbon radicals and cations, as well as iron(III) and iron(IV) oxidation states. The mechanisms involve state-specific product formation, as follows: a) The low-spin pathways lead to epoxide formation in effectively concerted mechanisms. b) The high-spin pathways have finite barriers for ring-closure and may have a sufficiently long lifetime to undergo rearrangement and lead to side products. c) The high-spin radical intermediate, (4)2(rad)-IV, has a ring closure barrier as small as the C--C rotation barrier. This intermediate will therefore lose stereochemistry and lead to a mixture of cis and trans epoxides. The barriers for the production of aldehyde and suicidal complexes are too high for this intermediate. d) The high-spin radical intermediate, (4)2(rad)-III, has a substantial ring closure barrier and may survive long enough time to lead to suicidal, phenacetaldehyde and 2-hydroxostyrene side products. e) The phenacetaldehyde and 2-hydroxostyrene products both originate from crossover from the (4)2(rad)-III radical intermediate to the cationic state, (4)2(cat,z(2) ). The process involves an N-protonated porphyrin intermediate that re-shuttles the proton back to the substrate to form either phenacetaldehyde or 2-hydroxostyrene products. This resembles the internally mediated NIH-shift observed during benzene hydroxylation.

Cytochrome P-450 Enzyme System↗
PubMed2005

The intrinsic axial ligand effect on propene oxidation by horseradish peroxidase versus cytochrome P450 enzymes.

The axial ligand effect on reactivity of heme enzymes is explored by means of density functional theoretical calculations of the oxidation reactions of propene by a model compound I species of horseradish peroxidase (HRP). The results are assessed vis-a-vis those of cytochrome P450 compound I. It is shown that the two enzymatic species perform C=C epoxidation and C-H hydroxylation in a multistate reactivity scenario with Fe(III) and Fe(IV) electromeric situations and two different spin states, doublet and quartet. However, while the HRP species preferentially keeps the iron in a low oxidation state (Fe(III)), the cytochrome P450 species prefers the higher oxidation state (Fe(IV)). It is found that HRP compound I has somewhat lower barriers than those obtained by the cytochrome P450 species. Furthermore, in agreement with experimental observations and studies on model systems, HRP prefers C=C epoxidation, whereas cytochrome P450 prefers C-H hydroxylation. Thus, had the compound I species of HRP been by itself, it would have been an epoxidizing agent, and at least as reactive as cytochrome P450. In the enzyme, HRP is much less reactive than cytochrome P450, presumably because HRP reactivity is limited by the access of the substrate to compound I.

Alkenes↗