A Valence Bond Modeling of Trends in Hydrogen Abstraction Barriers and Transition States of Hydroxylation Reactions Catalyzed by Cytochrome P450 Enzymes

Abstract

The paper outlines the fundamental factors that govern the mechanisms of alkane hydroxylation by cytochrome P450 and the corresponding barrier heights during the hydrogen abstraction and radical rebound steps of the process. This is done by a combination of density functional theory calculations for 11 alkanes and valence bond (VB) modeling of the results. The energy profiles and transition states for the various steps are reconstructed using VB diagrams (Shaik, S. S. J. Am. Chem. Soc. 1981, 103, 3692-3701. Shaik, S.; Shurki, A. Angew. Chem. Int. Ed. 1999, 38, 586-625.) and the DFT barriers are reproduced by the VB model from raw data based on C-H bond energies. The model explains a variety of other features of P450 hydroxylations: (a) the nature of the polar effect during hydrogen abstraction, (b) the difference between the activation mechanisms leading to the Fe(IV) vs the Fe(III) electromers, (c) the difference between the gas phase and the enzymatic reaction, and (d) the dependence of the rebound barrier on the spin state. The VB mechanism shows that the active species of the enzyme performs a complex reaction that involves multiple bond making and breakage mechanisms by utilizing an intermediate VB structure that cuts through the high barrier of the principal transformation between reactants and products, thereby mediating the process at a low energy cost. The correlations derived in this paper create order and organize the data for a process of a complex and important enzyme. This treatment can be generalized to the reactivity patterns of nonheme systems and synthetic iron-oxo porphyrin reagents.

Origin of the Correlation of the Rate Constant of Substrate Hydroxylation by Nonheme Iron(IV)–oxo Complexes with the Bond‐Dissociation Energy of the CH Bond of the Substrate

“…[14] As can be seen the correlation is fair for BDE CH and improves somewhat with addition of RE Sub to give a correlation of R 2 = 0.91.…”

“…[6] Discussion Recently, trends in hydrogen-abstraction barriers of a hemetype iron(IV)-oxo oxidant mimicking the active oxidant of P450 enzymes were explained with a VB curve-crossing diagram. [14] These studies rationalized why the reaction barriers and consequently rate constants correlate with the strength of the C À H bond of the substrate that is broken in the process. Similar trends have been reported from experimental rate constants for substrate hydroxylation by a range of different metal-oxo species.…”

“…To explain these trends, we constructed a valence bond (VB) curve-crossing mechanism for the reaction of the iron(IV)-oxo species of TauD with a C À H bond of a substrate (SubH) analogous to that reported for CpdI of P450 [14] and NOS. [34] Figure 8 displays the VB curve-crossing diagram from TauD in part a) and the comparative diagram for the iron(IV)-oxo species of P450 is shown in part b).…”

“…[13] Recently, using a valence-bond (VB) curve-crossing diagram the hydroxylation mechanism and in particular the initial hydrogen-abstraction step of heme-type iron(IV)-oxo oxidants as it appear in the P450s have been rationalized. [14] To establish what the fundamental factors are that drive the hydrogen abstraction and substrate hydroxylation mechanisms of nonheme iron(IV)-oxo oxidants and how it mechanisA C H T U N G T R E N N U N G ticA C H T U N G T R E N N U N G ally compares with heme-type iron(IV)-oxo oxidants, we have done a series of density functional theory (DFT) calculations on substrate hydroxylation by a nonheme iron(IV)-oxo oxidant mimicking the active site structure of TauD. Using a VB curve-crossing model trends in reaction patterns of substrate hydroxylation are described.…”

Biodegradation of Cosmetics Products: A Computational Study of Cytochrome P450 Metabolism of Phthalates

“…Therefore, the hydrogen atom abstraction barrier will be related to the strength of the σ CH orbital that needs to be broken, the strength of the σ OH orbital that is formed, the strength of the 3-electron π xz /π* xz -orbitals that need to be broken and the promotion energy from 2p O to a 2u . Indeed, previous studies of ours have shown that the hydrogen atom abstraction barriers for a series of substrates correlates with the bond dissociation energy (BDE) of the C-H bond that was broken [26,63,83,84]. To gain insight into the relative C-H bond strengths of the various aliphatic positions of the phthalate substrate, we calculated the BDE CH for all aliphatic positions as the diabatic energy between the substrate and the sum of the substrate minus a hydrogen atom and a hydrogen atom, see Figure 10.…”