Theoretical study of N-demethylation of substituted N,N-dimethylanilines by cytochrome P450: the mechanistic significance of kinetic isotope effect profiles

The mechanism of N-demethylation of N,N-dimethylanilines (DMAs) by cytochrome P450, a highly debated topic in mechanistic bioinorganic chemistry (Karki, S. B.; Dinnocenczo, J. P.; Jones, J. P.; Korzekwa, K. R. J. Am. Chem. Soc. 1995, 117, 3657), is studied here using DFT calculations of the reactions of the active species of the enzyme, Compound I (Cpd I), with four para-(H, Cl, CN, NO2) substituted DMAs. The calculations resolve mechanistic controversies, offer a consistent mechanistic view, and reveal the following features: (a) the reaction pathways involve C-H hydroxylation by Cpd I followed by a nonenzymatic carbinolamine decomposition. (b) C-H hydroxylation is initiated by a hydrogen atom transfer (HAT) step that possesses a "polar" character. As such, the HAT energy barriers correlate with the energy level of the HOMO of the DMAs. (c) The series exhibits a switch from spin-selective reactivity for DMA and p-Cl-DMA to two-state reactivity, with low- and high-spin states, for p-CN-DMA and p-NO2-DMA. (d) The computed kinetic isotope effect profiles (KIEPs) for these scenarios match the experimentally determined KIEPs. Theory further shows that the KIEs and TS structures vary in a manner predicted by the Melander-Westheimer postulate: as the substituent becomes more electron withdrawing, the TS is shifted to a later position along the H-transfer coordinate and the corresponding KIEs increases. (e) The generated carbinolaniline can readily dissociate from the heme and decomposes in a nonenzymatic environment, which involves water assisted proton shift.     

Hydrogen-abstraction reactivity patterns from A to Y: the valence bond way

"Give us insight, not numbers" was Coulson's admonition to theoretical chemists. This Review shows that the valence bond (VB)-model provides insights and some good numbers for one of the fundamental reactions in nature, the hydrogen-atom transfer (HAT). The VB model is applied to over 50 reactions from the simplest H + H(2) process, to P450 hydroxylations and H-transfers among closed-shell molecules; for each system the barriers are estimated from raw data. The model creates a bridge to the Marcus equation and shows that H-atom abstraction by a closed-shell molecule requires a higher barrier owing to the additional promotion energy needed to prepare the abstractor for H-abstraction. Under certain conditions, a closed-shell abstractor can bypass this penalty through a proton-coupled electron transfer (PCET) mechanism. The VB model links the HAT and PCET mechanisms conceptually and shows the consequences that this linking has for H-abstraction reactivity.     

Crowding games are sequentially solvable

A sequential-move version of a given normal-form game Γ is an extensive-form game of perfect information in which each player chooses his action after observing the actions of all players who precede him and the payoffs are determined according to the payoff functions in Γ. A normal-form game Γ is sequentially solvable if each of its sequential-move versions has a subgame-perfect equilibrium in pure strategies such that the players' actions on the equilibrium path constitute an equilibrium of Γ.  A crowding game is a normal-form game in which the players share a common set of actions and the payoff a particular player receives for choosing a particular action is a nonincreasing function of the total number of players choosing that action. It is shown that every crowding game is sequentially solvable. However, not every pure-strategy equilibrium of a crowding game can be obtained in the manner described above. A sufficient, but not necessary, condition for the existence of a sequential-move version of the game that yields a given equilibrium is that there is no other equilibrium that Pareto dominates it. Received July 1997/Final version May 1998     

Oriented (Local) Electric Fields Drive the Millionfold Enhancement of the H-Abstraction Catalysis Observed for Synthetic Metalloenzyme Analogues

This contribution follows the recent remarkable catalysis observed by Groves et al. in hydrogen-abstraction reactions by a) an oxoferryl porphyrin radical-cation complex [Por^⋅+Fe^IV(O)L_ax] and b) a hydroxoiron porphyrazine ferric complex [PyPzFe^III(OH)L_ax], both of which involve positively charged substituents on the outer circumference of the respective macrocyclic ligands. These charge-coronated complexes are analogues of the biologically important Compound I (Cpd I) and synthetic hydroxoferric species, respectively. We demonstrate that the observed enhancement of the H-abstraction catalysis for these systems is a purely electrostatic effect, elicited by the local charges embedded on the peripheries of the respective macrocyclic ligands. Our findings provide new insights into how electrostatics can be employed to tune the catalytic activity of metalloenzymes and can thus contribute to the future design of new and highly efficient hydrogen-abstraction catalysts.     

Can ferric-superoxide act as a potential oxidant in P450(cam)? QM/MM investigation of hydroxylation, epoxidation, and sulfoxidation

In view of recent reports of high reactivity of ferric-superoxide species in heme and nonheme systems (Morokuma et al. J. Am. Chem. Soc. 2010, 132, 11993-12005; Que et al. Inorg. Chem. 2010, 49, 3618-3628; Nam et al. J. Am. Chem. Soc. 2010, 132, 5958-5959; J. Am. Chem. Soc. 2010, 132, 10668-10670), we use herein combined quantum mechanics/molecular mechanics (QM/MM) methods to explore the potential reactivity of P450(cam) ferric-superoxide toward hydroxylation, epoxidation, and sulfoxidation. The calculations demonstrate that P450 ferric-superoxide is a sluggish oxidant compared with the high-valent oxoiron porphyrin cation-radical species. As such, unlike heme enzymes with a histidine axial ligand, the P450 superoxo species does not function as an oxidant in P450(cam). The origin of this different behavior of the superoxo species of P450 vis-a?-vis other heme enzymes like tryptophan 2, 3-dioxygenase (TDO) is traced to the ability of the latter superoxo species to make a stronger FeOO-X (X = H,C) bond and to stabilize the corresponding bond-activation transition states by resonance with charge-transfer configurations. By contrast, the negatively charged thiolate ligand in the P450 superoxo species minimizes the mixing of charge transfer configurations in the transition state and raises the reaction barrier. However, as we demonstrate, an external electric field oriented along the Fe-O axis with a direction pointing from Fe toward O will quench Cpd I formation by slowing the reduction of ferric-superoxide and will simultaneously lower the barriers for oxidation by the latter species, thereby enabling observation of superoxo chemistry in P450. Other options for nascent superoxo reactivity in P450 are discussed.     

Lorentz Invariant Berry Phase for a Perturbed Relativistic Four Dimensional Harmonic Oscillator

We show the existence of Lorentz invariant Berry phases generated, in the Stueckelberg–Horwitz–Piron manifestly covariant quantum theory (SHP), by a perturbed four dimensional harmonic oscillator. These phases are associated with a fractional perturbation of the azimuthal symmetry of the oscillator. They are computed numerically by using time independent perturbation theory and the definition of the Berry phase generalized to the framework of SHP relativistic quantum theory.