A new mechanism for ethanol oxidation mediated by cytochrome P450 2E1: bulk polarity of the active site makes a difference.
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Binding Sites↗
Biomedical subjects
Sason Shaik
Publications and source records attributed to Sason Shaik.
A survey of recent developments in ab initio valence bond theory.
Starting from the 1980s and onwards, Valence Bond theory has been enjoying renaissance that is characterized by the development of a growing number of ab initio methods, and by many applications to chemical reactivity and to the central paradigms of chemistry. Owing the increase of computational power of modern computers and to significant advances in the methodology, valence bond theory begins to offer a sound and attractive alternative to Molecular Orbital theory. This review aims at summarizing the most important developments of ab initio valence bond methods during the last two or three decades, and is primarily devoted to a description of what the various methods can actually achieve within their specific scopes and limitations. Key available softwares are surveyed.
Journal Article↗
A valence bond study of the dioxygen molecule.
The dioxygen molecule has been the subject of valence bond (VB) studies since 1930s, as it was considered as the first "failure" of VB theory. The object of this article is to provide an unambiguous VB interpretation for the nature of chemical bonding of the molecule by means of modern VB computational methods, VBSCF, BOVB, and VBCI. It is shown that though the VBSCF method can not provide quantitative accuracy for the strongly electronegative and electron-delocalized molecule because of the lack of dynamic correlation, it still gives a correct qualitative analysis for wave function of the molecule and provides intuitive insights into chemical bonding. An accurate quantitative description for the molecule requires higher levels of VB methods that incorporate dynamic correlation. The potential energy curves of the molecule are computed at the various VB levels. It is shown that there exists a small hump in the PECs of VBSCF for the ground state, as found in previous studies. However, higher levels of VB methods dissolve the hump. The BOVB and VBCI methods reproduce the dissociation energies and other physical properties of the ground state and the two lowest excited states in very good agreement with experiment and with sophisticated MO based methods, such as the MRCI method.
Algorithms↗
The Lewis legacy: the chemical bond--a territory and heartland of chemistry.
Is chemistry a science without a territory? I argue that "chemical bonding" has been a traditional chemical territory ever since the chemical community amalgamated in the seventeenth century, and even before. The modern charter of this territory is Gilbert Newton Lewis, who started the "electronic structure revolution in chemistry." As a tribute to Lewis, I describe here three of his key papers from the years 1913, 1916, and 1923, and analyze them. Lewis has defined the quantum unit, the "electron pair bond," for construction of a chemical universe, and in so doing he charted a vast chemical territory and affected most profoundly the mental map of chemistry for generations ahead. Nevertheless, not all is known about the chemical bond" the chemical territory is still teaming with new and exciting problems of in new materials, nanoparticles, quantum dots, metalloenzymes, bonding at surface-vapor interfaces, and so on and so forth.
Journal Article↗
Structure and quantum chemical characterization of chloroperoxidase compound 0, a common reaction intermediate of diverse heme enzymes.
We have determined the crystal structure of the chloroperoxidase (CPO) hydroperoxo reaction intermediate (CPO compound 0) at 1.75-A resolution. The intermediate was generated through controlled photoreduction of the CPO oxygen complex during x-ray data collection, which was monitored by recording of the crystal absorption spectra. Initially, the peroxo-anion species was formed and then protonated to yield compound 0. Quantum chemical calculations indicate that the peroxo-anion species is not stable and collapses instantaneously to compound 0. Compound 0 is present in the ferric low-spin doublet ground state and is characterized by a long O O bond length of 1.5 A and a Fe O bond distance of 1.8 A, which is also observed in the crystal structure.
Binding Sites↗
Proton-shuffle mechanism of O-O activation for formation of a high-valent oxo-iron species of bleomycin.
Bleomycins (BLMs) can utilize H2O2 to cleave DNA in the presence of ferric ions. DFT calculations were used to study the mechanism of O-O bond cleavage in the low-spin FeIII-hydroperoxo complex of BLM. The following alternative hypotheses were investigated using realistic structural models: (a) heterolytic cleavage of the O-O bond, generating a Compound I (Cpd I) like intermediate, formally BLM-FeV=O; (b) homolytic O-O cleavage, leading to a BLM-FeIV=O species and an OH* radical; and (c) a direct O-O cleavage/H-abstraction mechanism by ABLM. The calculations showed that (a) is a facile and viable mechanism; it involves acid-base proton reshuffle mediated by the side-chain linkers of BLM, causing thereby heterolytic cleavage of the O-O bond and generation of Cpd I. Formation of Cpd I is found to involve a barrier of 13.3 kcal/mol, which is lower than the barriers in the alternative mechanisms (b and c) that possess respective barriers of 31 and 17 kcal/mol. The so-formed Cpd I species with a radical on the side-chain linker, methylvalerate (V), adjacent to the BLM-FeIV=O complex, resembles the formation of the active species of cytochrome c peroxidase in the Poulos-Kraut proton-shuffle mechanism in heme peroxidases (Poulos, T. L.; Kraut, J. J. Biol. Chem. 1980, 255, 8199-8205). Experimental data are discussed and shown to be in accord with this proposal. It suggests that the high-valence Cpd I species of BLM participates in the DNA cleavage. This is an alternative mechanistic hypothesis to the exclusive reactivity scenario based on ABLM (FeIII-OOH).
Bleomycin↗
Characterization of manganese(V)-oxo polyoxometalate intermediates and their properties in oxygen-transfer reactions.
A manganese(III)-substituted polyoxometalate, [alpha2-P2MnIII(L)W17O61]7- (P2W17MnIII), was studied as an oxidation catalyst using iodopentafluorobenzene bis(tifluoroacetate) (F5PhI(TFAc)2) as a monooxygen donor. Pink P2W17MnIII turns green upon addition of F5PhI(TFAc)2. The 19F NMR spectrum of F5PhI(TFAc)2 with excess P2W17MnIII at -50 degrees C showed the formation of an intermediate attributed to P2W17MnIII-F5PhI(TFAc)2 that disappeared upon warming. The 31P NMR spectra of P2W17MnIII with excess F5PhI(TFAc)2 at -50 and -20 degrees C showed a pair of narrow peaks attributed to a diamagnetic, singlet manganese(V)-oxo species, P2W17MnV=O. An additional broad peak at -10.6 ppm was attributed to both the P2W17MnIII-F5PhI(TFAc)2 complex and a paramagnetic, triplet manganese(V)-oxo species. The electronic structure and reactivity of P2W17MnV=O were modeled by DFT calculations using the analogous Keggin compound, [PMnV=OW11O39]4-. Calculations with a pure functional, UBLYP, showed singlet and triplet ground states of similar energy. Further calculations using both the UBLYP and UB3LYP functionals for epoxidation and hydroxylation of propene showed lowest lying triplet transition states for both transformations, while singlet and quintet transition states were of higher energy. The calculations especially after corrections for the solvent effect indicate that [PMnV=OW11O39]4- should be highly reactive, even more reactive than analogous MnV=O porphyrin species. Kinetic measurements of the reaction of P2W17MnV=O with 1-octene indicated, however, that P2W17MnV=O was less reactive than a MnV=O porphyrin. The experimental enthalpy of activation confirmed that the energy barrier for epoxidation is low, but the highly negative entropy of activation leads to a high free energy of activation. This result originates in our view from the strong solvation of the highly charged polyoxometalate by the polar solvent used and adventitious water. The higher negative charge of the polyoxometalate in the transition versus ground state leads to electrostriction of the solvent molecules and to a loss of degrees of freedom, resulting in a highly negative entropy of activation and slower reactions.
Journal Article↗
An efficient proton-coupled electron-transfer process during oxidation of ferulic acid by horseradish peroxidase: coming full cycle.
Quantum mechanics/molecular mechanics calculations were utilized to study the process of oxidation of a native substrate (ferulic acid) by the active species of horseradish peroxidase (Dunford, H. B. Heme Peroxidases; Wiley-VCH: New York, 1999), Compound I and Compound II, and the manner by which the enzyme returns to its resting state. The results match experimental findings and reveal additional novel features. The calculations demonstrate that both oxidation processes are initiated by a proton-coupled electron-transfer (PCET) step, in which the active species of the enzyme participate only as electron-transfer partners, while the entire proton-transfer event is being relayed from the substrate to and from the His42 residue by a water molecule (W402). The reason for the observed (Henriksen, A; Smith, A. T.; Gajhede, M. J. Biol. Chem. 1999, 274, 35005-35011) similar reactivities of Compound I and Compound II toward ferulic acid is that the reactive isomer of Compound II is the, hitherto unobserved, Por(*)(+)Fe(III)OH isomer that resembles Compound I. The PCET mechanism reveals that His42 and W402 are crucial moieties and they determine the function of the HRP enzyme and account for its ability to perform substrate oxidation (Poulos, T. L. Peroxidases and Cytochrome P450. In The Porphyrin Handbook; Kadish, K. M., Smith, K. M., Guilard, R., Eds.; Academic Press: New York, 2000; Vol. 4, pp 189). In view of the results, the possibility of manipulating substrate oxidation by magnetic fields is an intriguing possibility.
Algorithms↗
Catalysts for monooxygenations made from polyoxometalate: an iron(V)-oxo derivative of the Lindqvist anion.
This work uses density functional calculations to design a new high-valent Fe(V)=O catalyst [Mo5O18Fe=O]3-, which is based on the Lindqvist polyoxometalate (Mo6O19(2-)). Because the parent species is stable to oxidative conditions, one may assume that the newly proposed iron-oxo species will be stable, too. The calculated Mössbauer spectroscopic data may be helpful toward an eventual identification of the species. The calculations of C-H hydroxylation and C=C epoxidation of propene show that, if made, [Mo5O18Fe=O]3- should be a potent oxidant that will be subject to strong solvent effect. Moreover, the Lindqvist catalyst leads to an intriguing result; the reaction that starts along an epoxidation pathway with C=C activation ends with a C-H hydroxylation product ((4)6) due to rearrangement on the catalyst. The origins of this result are analyzed in terms of the structure of the catalyst and the electronic requirements for conversion of an epoxidation intermediate to a hydroxylation product. Thus, if made, the [Mo5O18Fe=O]3 will be a selective C-H hydroxylation reagent.
Journal Article↗
QM/MM study of mechanisms for compound I formation in the catalytic cycle of cytochrome P450cam.
In the catalytic cycle of cytochrome P450cam, after molecular oxygen binds as a ligand to the heme iron atom to yield a ferrous dioxygen complex, there are fast proton transfers that lead to the formation of the active species, Compound I (Cpd I), which are not well understood because they occur so rapidly. In the present work, the conversion of the ferric hydroperoxo complex (Cpd 0) to Cpd I has been investigated by combined quantum-mechanical/molecular-mechanical (QM/MM) calculations. The residues Asp(251) and Glu(366) are considered as proton sources. In mechanism I, a proton is transported to the distal oxygen atom of the hydroperoxo group via a hydrogen bonding network to form protonated Cpd 0 (prot-Cpd0: FeOOH(2)), followed by heterolytic O-O bond cleavage that generates Cpd I and water. Although a local minimum is found for prot-Cpd0 in the Glu(366) channel, it is very high in energy (more than 20 kcal/mol above Cpd 0) and the barriers for its decay are only 3-4 kcal/mol (both toward Cpd 0 and Cpd I). In mechanism II, an initial O-O bond cleavage followed by a concomitant proton and electron transfer yields Cpd I and water. The rate-limiting step in mechanism II is O-O cleavage with a barrier of about 13-14 kcal/mol. According to the QM/MM calculations, the favored low-energy pathway to Cpd I is provided by mechanism II in the Asp(251) channel. Cpd 0 and Cpd I are of similar energies, with a slight preference for Cpd I.
Camphor 5-Monooxygenase↗
Identity SN2 reactions X- + CH3X --> XCH3 + X- (X=F, Cl, Br, and I) in vacuum and in aqueous solution: a valence bond study.
The recently developed (L. Song, W. Wu, Q. Zhang, S. Shaik, J. Phys. Chem. A 2004, 108, 6017) valence bond method coupled with a polarized continuum model (VBPCM) has been applied to the identity SN2 reaction of halides in the gas phase and in aqueous solution. The barriers computed at the level of the breathing orbital VB method (P. C. Hiberty, J. P. Flament, E. Noizet, Chem. Phys. Lett. 1992, 189, 259), BOVB and VBPCM//BOVB, are comparable to CCSD(T) and CCSD(T)//PCM results and to experimentally derived barriers in solution (W. J. Albery, M. M. Kreevoy, Adv. Phys. Org. Chem. 1978, 16, 85). The reactivity parameters needed to apply the valence bond state correlation diagram (VBSCD) method (S. Shaik, J. Am. Chem. Soc. 1984, 106, 1227), were also determined by VB calculations. It has been shown that the reactivity parameters along with their semiempirical derivations provide a satisfactory qualitative and quantitative account of the barriers.
Computer Simulation↗
On the identity and reactivity patterns of the "second oxidant" of the T252A mutant of cytochrome P450cam in the oxidation of 5-methylenenylcamphor.
Density functional calculations show that in the absence of Compound I, the primary oxidant species of P450, the precursor species, Compound 0 (FeOOH), can effect double bond activation of 5-methylenylcamphor (1). The mechanism is initiated by homolytic cleavage of the O-O bond and formation of an OH radical bound to the Compound II species by hydrogen bonding interactions. Subsequently, the so-formed OH radical can either activate the double bond of 1 or attack the meso position of the heme en route to heme degradation. The calculations show that double bond activation is preferred over attack on the heme. Past the double bond activation, the intermediate can either lead to epoxidation or to a glycol formation. The glycol formation is predicted to be preferred, although in the P450(cam) pocket the competition may be closer. Therefore, in the absence of Compound I, Compound 0 will be capable of epoxidizing double bonds. Previous studies [E. Derat, D. Kumar, H. Hirao, S. Shaik, J. Am. Chem. Soc. 128 (2006) 473-484] showed that in the case of a substrate that can undergo only C-H activation, the bound OH prefers heme degradation over hydrogen abstraction. Since the epoxidation barrier for Compound I is much smaller than that of Compound 0 (12.8 vs. 18.9kcal/mol), when Compound I is present in the cycle, Compound 0 will be silent. As such, our mechanism explains lucidly why T252A P450(cam) can epoxidize olefins like 5-methylenylcamphor but is ineffective in camphor hydroxylation [S. Jin, T.M. Makris, T. A. Bryson, S.G. Sligar, J.H. Dawson, J. Am. Chem. Soc. 125 (2003) 3406-3407]. Our calculations show that the glycol formation is a marker reaction of Compound 0 with 5-methylenylcamphor. If this product can be found in T252A P450(cam) or in similar mutants of other P450 isozymes, this will constitute a more definitive proof for the action of Cpd 0 in P450 enzymes.
Alkenes↗
Does substrate oxidation determine the regioselectivity of cyclohexene and propene oxidation by cytochrome p450?
DFT and QM/MM computations of allylic C-H hydroxylation versus C=C epoxidation in cyclohexene and propene by Compound I of P450cam demonstrate that the relative barriers for the oxidative processes themselves are not good predictors of the observed selectivity. However, a kinetic expression previously developed (Kozuch, S.; Shaik, S. J. Am. Chem. Soc. 2006, 128, 3355) for catalytic cycles under steady-state conditions, predicts, in accord with experiment, that propene will undergo exclusive C=C epoxidation, while cyclohexene will undergo both reactions with a small preference for epoxidation. The model expression for the effective barrier of the cycle forms a general basis for understanding and predicting the selectivity of P450 isozymes.
Alkenes↗
Ferromagnetic bonding: high spin copper clusters (n+1)Cu(n); n = 2-14) devoid of electron pairs but possessing strong bonding.
Density functional theoretic studies are performed for the high-spin copper clusters (n)(+1)Cu(n) (n = 2-14), which are devoid of electron pairs shared between atoms, hence no-pair clusters (J. Phys. Chem. 1988, 92, 1352; Isr. J. Chem. 1993, 33, 455; J. Am. Chem. Soc. 1999, 121, 3165). Despite the lack of electron pairing, it is found that the bond dissociation energy per atom (BDE/n) is significant and converges (to within 1 kcal mol(-1)), around a cluster size (11)Cu(10), to a value of BDE/n = 19 kcal mol(-1). This is a very large bonding energy, much larger than has previously been obtained for no-pair clusters of lithium, BDE/n = 12 kcal mol(-1), or sodium clusters, BDE/n = 3 kcal mol(-1). This bonding, so-called ferromagnetic bonding (FM-bonding) is analyzed using a valence bond (VB) model (J. Phys. Chem. A 2002, 106, 4961; Phys. Chem. Chem. Phys. 2003, 5, 158). As such, FM-bonding in no-pair clusters is described as an ionic fluctuation, of the triplet pair, that spreads over all the close neighbors of a given atom in the clusters. Thus, if we refer to each triplet pair and its ionic fluctuations as a local FM-bond, we can regard the electronic structure of a given (n)(+1)M(n) cluster as a resonance hybrid of all the local FM-bonds between close neighbors. The model shows how a weak interaction in the diatomic triplet molecule can become a remarkably strong binding force that binds together mono-valent atoms without even a single electron pair. This is achieved because the growing number of VB structures exerts a cumulative effect of stabilization that is maximized when the cluster has a compact structure with an optimal coordination number for the atoms.
Benzoates↗
Two-state reactivity in alkane hydroxylation by non-heme iron-oxo complexes.
Density functional theory is used to explore the mechanisms of alkane hydroxylation for four synthetic non-heme iron(IV)-oxo complexes with three target substrates (Kaizer, J.; Klinker, E. J.; Oh, N. Y.; Rohde; J.-U.; Song, W. J.; Stubna, A.; Kim, J.; Münck, E.; Nam, W.; Que, L., Jr. J. Am. Chem. Soc. 2004, 126, 472-473; Rohde, J.-U.; Que, L., Jr. Angew. Chem. Int. Ed. 2005, 44, 2255-2258.). The iron-oxo reagents possess triplet ground states and low-lying quintet excited states. The set of experimental and theoretical reactivity trends can be understood if the reactions proceed on the two spin states, namely two-state reactivity (TSR); an appropriate new model is presented. The TSR model makes testable predictions: (a) If crossing to the quintet state occurs, the hydroxylation will be effectively concerted; however, if the process transpires only on the triplet surface, stepwise hydroxylation will occur, and side products derived from radical intermediates would be observed (e.g., loss of stereochemistry). (b) In cases of crossing en route to the quintet transition state, one expects kinetic isotope effects (KIEs) typical of tunneling. (c) In situations where the two surfaces contribute to the rate, one expects intermediate KIEs and radical scrambling patterns that reflect the two processes. (d) Solvent effects on these reactions are expected to be very large.
Alkanes↗
Two-state reactivity, electromerism, tautomerism, and "surprise" isomers in the formation of compound II of the enzyme horseradish peroxidase from the principal species, compound I.
QM and QM/MM calculations on Compound II, the enigmatic species in the catalytic cycle of the horseradish peroxidase enzyme, reveal six low-lying isomers. The principal isomer is the triplet oxo-ferryl form (PorFe(IV)=O) that yields the hydroxo-ferryl isomer (PorFe(IV)-OH+). These are the only forms observed in experimental studies. Theory shows, however, that these are the least stable isomers of Compound II. The two most stable forms are the singlet and triplet states of the Por+*Fe(III)-OH electromer. In addition, theory reveals species never considered in heme enzymes: the singlet and triplet states of the Por+*Fe(III)-OH2 electromer. The computational results reproduce the experimental features of the known isomers and enable us to draw relationships and make predictions regarding the missing ones. For example, while the "surprise" species, singlet and triplet Por+*Fe(III)-OH2, have never been considered in heme chemistry, the calculated Fe-O bond lengths indicate that these isomers may have, in fact, been observed in one of the two opposing EXAFS studies reported previously. Furthermore, these ferric-aqua complexes could be responsible for the reported 18O exchange with bulk water. It is clear, therefore, that the role of Compound II in the HRP cycle is considerably more multi-faceted than has been revealed so far. Our suggested multi-state reactivity scheme provides a paradigm for Compound II species. The calculated Mössbauer parameters may be helpful toward eventual characterization of these missing isomers of Compound II.
Computer Simulation↗
The Poulos-Kraut mechanism of Compound I formation in horseradish peroxidase: a QM/MM study.
QM/MM calculations are used to elucidate the Poulos-Kraut (Poulos, T. L.; Kraut, J. J. Biol. Chem. 1980, 255, 8199-8205) mechanism of O-O bond activation and Compound I (Cpd I) formation in HRP, in conditions corresponding to neutral to basic pH. Attempts to generate Compound I directly from the Fe(H2O2) complex by migrating the proton from the proximal oxygen to the distal one (1,2- proton shift) result in high barriers. The lowest energy mechanism was found to involve initial deprotonation of ferric hydrogen peroxide complex (involving spin crossover from the quartet to the doublet state) by His42 to form ferric-hydroperoxide (Cpd 0). Subsequently, the distal OH group of Cpd 0 is pulled by Arg38 and reprotonated by His42(H+) to form Cpd I and a water molecule that bridges the two residues. The structures of the intermediate and the transition state reveal the manner by which the Arg-His residues promote cooperatively the electronic reorganization that is required to attend the heterolytic O-O cleavage.
Ferric Compounds↗
Theoretical analysis of the structural and electronic properties of metalloporphyrin pi-cation radicals.
A method for analyzing the A(1u)/A(2u) contents of metalloporphyrin pi-cation radicals is developed and applied to a series of unsubstituted planar metalloporphines (MPs) (M=Cr, Mn, Fe, Co, Ni, Cu, and Zn). The structures and electronic properties of the MPs and their cation radicals were calculated by density functional theory (DFT) and subsequently analyzed. It was found that the MPs with small core sizes have a tendency to form A(1u)-type radicals, while the MPs with large core size have a preference for an A(2u)-type. Neither of these pure-state species, however, is stable under the D(4)(h) symmetry, and both radical cation types are subject to pseudo-Jahn-Teller (pJT) distortion. The pJT distortion leads to structures with lower symmetry and states that have mixed character with respect to the A(1u) and A(2u) components. The degree of mixing could be estimated by employing orbital projection technique or a complementary spin density decomposition. Both techniques produce very similar results, pointing out that the frontier orbital, which becomes empty upon electron removal, plays a critical role in determining electronic properties.
Algorithms↗