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Jeremy N Harvey

Publications and source records attributed to Jeremy N Harvey.

At least 19 recordsLinked to original sources
PubMed2006

Understanding the kinetics of spin-forbidden chemical reactions.

Many chemical reactions involve a change in spin-state and are formally forbidden. This article summarises a number of previously published applications showing that a form of Transition State Theory (TST) can account for the kinetics of these reactions. New calculations for the emblematic spin-forbidden reaction HC + N(2) are also reported. The observed reactivity is determined by two factors. The first is the critical energy required for reaction to occur, which in spin-forbidden reactions is often defined by the relative energy of the Minimum Energy Crossing Point (MECP) between potential energy surfaces corresponding to the different spin states. The second factor is the probability of hopping from one surface to the other in the vicinity of the crossing region, which is largely defined by the spin-orbit coupling matrix element between the two electronic wavefunctions. The spin-forbidden transition state theory takes both factors into account and gives good results. The shortcomings of the theory, which are largely analogous to those of standard TST, are discussed. Finally, it is shown that in cases where the surface-hopping probability is low, the kinetics of spin-forbidden reactions will be characterised by unusually unfavourable entropies of activation. As a consequence, reactions involving a spin-state change can be expected to compete poorly with spin-allowed reactions at high temperatures (or energies).

Journal Article↗
PubMed2006

Conformational effects in enzyme catalysis: reaction via a high energy conformation in fatty acid amide hydrolase.

Quantum mechanics/molecular mechanics and molecular dynamics simulations of fatty acid amide hydrolase show that reaction (amide hydrolysis) occurs via a distinct, high energy conformation. This unusual finding has important implications for fatty acid amide hydrolase, a key enzyme in the endocannabinoid system. These results demonstrate the importance of structural fluctuations and the need to include them in the modeling of enzyme reactions. They also show that approaches based simply on studying enzyme-substrate complexes can be misleading for understanding biochemical reactivity.

Amidohydrolases↗
PubMed2006

Mechanisms of reaction in cytochrome P450: Hydroxylation of camphor in P450cam.

The fundamental nature of reactivity in cytochrome P450 enzymes is currently controversial. Modelling of bacterial P450cam has suggested an important role for the haem propionates in the catalysis, though this finding has been questioned. Understanding the mechanisms of this enzyme family is important both in terms of basic biochemistry and potentially in the prediction of drug metabolism. We have modelled the hydroxylation of camphor by P450cam, using combined quantum mechanics/molecular mechanics (QM/MM) methods. A set of reaction pathways in the enzyme was determined. We were able to pinpoint the source of the discrepancies in the previous results. We show that when a correct ionization state is assigned to Asp297, no spin density appears on the haem propionates and the protein structure in this region remains preserved. These results indicate that the haem propionates are not involved in catalysis.

Aspartic Acid↗
PubMed2006

Reactivity and selectivity in the Wittig reaction: a computational study.

The salt-free Wittig reaction of non-, semi-, and stabilized ylides has been investigated on realistic systems using density functional theory (DFT) calculations, including continuum solvation. Our results provide unequivocal support for the generally accepted mechanism and are in very good agreement with experimental selectivities. This study shows that E/Z selectivity of non- and semi-stabilized ylides cannot be fully understood without considering the energy of the elimination TS. The influence of ylide stabilization and the nature of phosphorus substituents on reversibility of oxaphosphetane formation is clarified. Unexpectedly, the puckering ability of addition TSs is shown not to depend on ylide stabilization, but the geometry of the TS is decided by an interplay of 1,2; 1,3; and C-H...O interactions in the case of non- and semi-stabilized ylides, whereas a dipole-dipole interaction governs the addition TS structures for stabilized ylides. The well-known influence of ylide stabilization on selectivity of PPh(3) derivatives is explained as follows: in non- and semi-stabilized ylides reactions, cis and trans addition TSs have, respectively, puckered and planar geometries, and selectivity is governed by an interplay of 1,2 and 1,3 interactions. For stabilized ylides, the high E selectivity is due to a strong dipole-dipole interaction at the addition TS. The influence of the nature of phosphorus substituents on selectivity is also detailed, the different behavior of (MeO)(3)PCHCO(2)Me ylides being explained by their lower dipole. This novel picture of the factors determining TS structures and selectivity provides a sound basis for the design of new ylides.

Journal Article↗
PubMed2006

Highly enantioselective synthesis of glycidic amides using camphor-derived sulfonium salts. Mechanism and applications in synthesis.

The reactions of a range of amide-stabilized sulfur ylides derived from readily available camphor-derived sulfonium salts for the synthesis of glycidic amides have been studied. Primary, secondary, and tertiary amides were tested, and it was found that the highest enantioselectivities were observed with tertiary amides, which provided glycidic amides in good to excellent yields, exclusive trans selectivity, and excellent enantioselectivities. The reaction was general for aromatic aldehydes, but aliphatic aldehydes gave more variable enantioselectivities. The epoxy amides could be converted cleanly into epoxy ketones by treatment with organolithium reagents. We were also able to effect selective ring opening of the epoxy amides with a variety of nucleophiles, followed by hydrolysis of the amide to yield the corresponding carboxylic acid. This methodology was applied to the total synthesis of the target compound SK&F 104353. A combination of crossover experiments and theoretical calculations has revealed that the rate- and selectivity-determining step is ring closure, not betaine formation as was the case for phenyl-stabilized ylides.

Amides↗
PubMed2006

Is phenyl a good migrating group in the rearrangement of organoborates generated from sulfur ylides?

Calculations show that the unexpected low phenyl migratory aptitude observed in reactions of mixed alkyl-aryl boranes with benzylic sulfur ylides can be attributed to (1) a conformational issue, (2) the reduction of the usual neighbouring effect of the phenyl in the transition state by the benzylic nature of the migrating terminus, (3) steric hindrance suffered by the larger phenyl group migrating to the hindered migrating terminus and this despite (4) the increase in the barrier to alkyl migration by the presence of a 'non-migrating' phenyl on the boron atom.

Alkanes↗
PubMed2006

Raman spectroscopy of diamondoids.

A selection of diamondoid hydrocarbons, from adamantane to [121321] heptamantane, have been analysed by multi-wavelength laser Raman spectroscopy. Spectra were assigned using vibrational frequencies and Raman intensities were calculated by employing the B3LYP functional and the split valence basis set of Schafer, Horn and Ahlrichs with polarisation functions on carbon atoms. The variation of the spectra and associated vibrational modes with the structure and symmetry of the molecules are discussed. Each diamondoid was found to produce a unique Raman spectrum, allowing for easy differentiation between molecules. Using the peak assignments derived from the calculations we find that the low frequency region of the spectra, corresponding to CCC-bending/CC-stretching modes, is particularly characteristic of the geometric shape of the diamondoid molecules.

Adamantane↗
PubMed2006

QM/MM modeling of compound I active species in cytochrome P450, cytochrome C peroxidase, and ascorbate peroxidase.

QM/MM calculations provide a means for predicting the electronic structure of the metal center in metalloproteins. Two heme peroxidases, Cytochrome c Peroxidase (CcP) and Ascorbate Peroxidase (APX), have a structurally very similar active site, yet have active intermediates with very different electronic structures. We review our recent QM/MM calculations on these systems, and present new computational data. Our results are in good agreement with experiment, and suggest that the difference in electronic structure is due to a large number of small differences in structure from one protein to another. We also discuss recent QM/MM calculations on the active species of cytochrome P450, in which a similar sensitivity of the electronic structure to the environment is found. However, this does not appear to explain different catalytic profiles of the different drug-metabolizing isoforms of this class of enzyme.

Ascorbate Peroxidases↗
PubMed2005

The Fe-CO bond energy in myoglobin: a QM/MM study of the effect of tertiary structure.

The Fe-CO bond dissociation energy (BDE) in myoglobin (Mb) has been calculated with B3LYP quantum mechanics/molecular mechanics methods for 22 different Mb conformations, generated from molecular dynamics simulations. Our average BDE of 8.1 kcal/mol agrees well with experiment and shows that Mb weakens the Fe-CO bond by 5.8 kcal/mol; the calculations provide detailed atomistic insight into the origin of this effect. BDEs for Mb conformations with the R carbonmonoxy tertiary structure are on average 2.6 kcal/mol larger than those with the T deoxy tertiary structure, suggesting two functionally distinct allosteric states. This allostery is partly explained by the reduction in distal cavity steric crowding as Mb moves from its T to R tertiary structure.

Animals↗
PubMed2005

Development of a ligand knowledge base, part 1: computational descriptors for phosphorus donor ligands.

A prototype collection of knowledge on ligands in metal complexes, termed a ligand knowledge base (LKB), has been developed. This contribution describes the design of DFT-calculated descriptors for monodentate phosphorus(III) donor ligands in a range of representative complexes. Using the resulting data, a ligand space is mapped and predictive models are derived for metal complexes. Important characteristics, including chemical, computational and statistical robustness for the generation and exploitation of such an LKB are described. Chemical robustness ensures transferability of the descriptors, as well as comprehensive sampling of ligand space. To make the calculations amenable to automation in an e-science setting, a reliable, well-defined computational approach has been sought from which the descriptors can be readily extracted. The LKB has been explored with multivariate statistical methods. Principal component analysis (PCA) is used for the mapping of chemical space, projecting multiple descriptors into scatter plots which illustrate the clustering of chemically similar ligands. Interpretation of the resulting principal components in terms of established steric and electronic properties and the importance of its statistical robustness to variations in the ligand set are discussed. Multiple linear regression (MLR) models have been derived, demonstrating the versatility of the descriptors for modeling varied experimentally determined parameters (bond lengths, reaction enthalpies and bond-stretching frequencies). The importance of re-sampling methods for testing the robustness of predictions is highlighted. A strategy for the construction of a robust LKB suitable for the modeling of ligand and complex behavior is outlined based on these observations.

Journal Article↗
PubMed2005

Computational study of the energetics of 3Fe(CO)4, 1Fe(CO)4 and 1Fe(CO)4(L), L = Xe, CH4, H2 and CO.

Large basis CCSD(T) calculations are used to calculate the energetics of 3Fe(CO)4, 1Fe(CO)4 and 1Fe(CO)4(L), L = Xe, CH4, H2 and CO. . The relative energy of the excited singlet state of Fe(CO)4 with respect to the ground triplet state is not known experimentally, and various lower levels of theory predict very different results. Upon extrapolating to the infinite basis set limit, and including corrections for core-core and core-valence correlation, scalar relativity, and multi-reference character of the wavefunction, the best CCSD(T) estimate for the spin-state splitting in iron tetracarbonyl is 2 kcal mol(-1). Calculation of the dissociation energy of 1Fe(CO)4(L) into singlet fragments, taken together with known experimental behaviour of triplet Fe(CO)4, provides independent evidence for the fact that the spin-state splitting is smaller than 3 kcal mol(-1). These calculations highlight some of the challenges involved in benchmark calculations on transition metal containing systems.

Carbon Monoxide↗
PubMed2005

On the origin of high E selectivity in the Wittig reaction of stabilized ylides: importance of dipole-dipole interactions.

The salt-free Wittig reaction of stabilized ylides Ph3PCHCO2Me 1 and (MeO)3PCHCO2Me 2 has been investigated using DFT method including solvation. This analysis shows that TS structures and E/Z selectivity in the phosphine stabilized ylide 1, which gives high E selectivity with PhCHO, are predominantly controlled by a dipole-dipole interaction between the two reactants at the TS (as well as the well-known 1,2 and 1,3 steric interactions). The surprisingly different behavior of the phosphite ylide 2, which gives only 69:31 E/Z ratio with PhCHO, is accounted for by its much smaller overall dipole. The introduction of this new parameter (dipole-dipole interactions), which has not previously been invoked in discussions of this important reaction, accommodates all the experimental observations relating to selectivity in the Wittig reaction of stabilized ylides under salt-free conditions.

Journal Article↗
PubMed2005

Electronic structure of compound I in human isoforms of cytochrome P450 from QM/MM modeling.

Human cytochromes P450 play a vital role in drug metabolism. The key step in substrate oxidation involves hydrogen atom abstraction or C=C bond addition by the oxygen atom of the Compound I intermediate. The latter has three unpaired electrons, two on the Fe-O center and one shared between the porphyrin ring and the proximal cysteinyl sulfur atom. Changes in its electronic structure have been suggested to affect reactivity. The electronic and geometric structure of Compound I in three important human subfamilies of cytochrome P450 (P450, 2C, 2B, and 3A) that are major contributors to drug metabolism is characterized here using combined quantum mechanical/molecular mechanical (QM/MM) calculations at the B3LYP:CHARMM27 level. Compound I is remarkably similar in all isoforms, with the third unpaired electron located mainly on the porphyrin ring, and this prediction is not very sensitive to details of the QM/MM methodology, such as the DFT functional, the basis set, or the size of the QM region. The presence of substrate also has no effect. The main source of variability in spin density on the cysteinyl sulfur (from 26 to 50%) is the details of the system setup, such as the starting protein geometry used for QM/MM minimization. This conformational effect is larger than the differences between human isoforms, which are therefore not distinguishable on electronic grounds, so it is unlikely that observed large differences in substrate selectivity can be explained to a large extent in these terms.

Crystallography, X-Ray↗
PubMed2005

QM/MM studies of the electronic structure of the compound I intermediate in cytochrome c peroxidase and ascorbate peroxidase.

Cytochrome c peroxidase (CcP) and ascorbate peroxidase (APX) both involve reactive haem oxoferryl intermediates known as 'compound I' species. These two enzymes also have a very similar structure, especially in the vicinity of the haem group. Despite this similarity, the electronic structure of compound I in the two enzymes is known to be very different. Compound I intermediates have three unpaired electrons, two of which are always situated on the Fe-O core, whilst the third is located in a porphyrin orbital in APX and many other compound I species. In CcP, however, this third unpaired electron is positioned on a tryptophan residue lying close to the haem ring. The same residue is present in the same position in APX, yet it is not oxidized in that case. We report QM/MM calculations, using accurate B3LYP density functional theory for the QM region, on the active intermediate for both enzymes. We reproduce the observed difference in electronic structure, and show that it arises as a result of subtle electrostatic effects which affect the ionization potential of both the tryptophan and porphyrin groups. The computed structures of both enzymes do not involve deprotonation of the tryptophan group, or protonation of the oxoferryl oxygen.

Ascorbate Peroxidases↗
PubMed2005

Multiple high-level QM/MM reaction paths demonstrate transition-state stabilization in chorismate mutase: correlation of barrier height with transition-state stabilization.

Multiple profiles for the reaction from chorismate to prephenate in the enzyme chorismate mutase calculated with hybrid density functional combined quantum mechanics/molecular mechanics methods (B3LYP/6-31G(d)-CHARMM27) agree well with experiment, and provide direct evidence of transition-state stabilization by this important enzyme, which is at the centre of current debates about the nature of enzyme catalysis.

Chorismate Mutase↗
PubMed2005

Substituent effects and the mechanism of alkene metathesis catalyzed by ruthenium dichloride catalysts.

Density functional theory calculations are reported concerning the dissociative mechanism for alkene metathesis by ruthenium dichloride catalysts, including both bisphosphine and diaminocarbene/phosphine complexes. The calculations use a hierarchy of models, ranging from [(L)(PH(3))Ru(Cl)(2)(CH(2))](L=PH(3) or diaminocarbene) through the larger [(L)(PMe(3))Ru(Cl)(2)(CHPh)] to the "real"[(L)(PCy(3))Ru(Cl)(2)(CHPh)]. Calculations show that the rate-limiting step for metathesis is either ring closing from an alkene complex to form a ruthena-cyclobutane, or ring-opening of the latter intermediate to form an isomeric alkene complex. The higher efficiency of the diaminocarbene based catalysts is due to the stabilization of the formal +iv oxidation state of the ruthenium centre in the metallacycle. This effect is partly masked in the smaller model systems due to a previously unnoticed stereoelectronic effect. The calculations do not reproduce the experimental observation whereby the initiation step, phosphine dissociation, is more energetically demanding and hence slower for the diaminocarbene-containing catalyst system than for the bisphosphine. Further calculations on the corresponding bond energies using a variety of DFT and hybrid DFT/molecular mechanics methods all find instead a larger phosphine dissociation energy for the bisphosphine catalyst. This reversed order of binding energies would in fact be the one expected based on the stronger trans influence of the diaminocarbene ligand. The discrepancy with experiment is small and could have a number of causes which are discussed here.

Journal Article↗