Water-Assisted Oxo Mechanism for Heme Metabolism

A mechanism of heme metabolism by heme oxygenase (HO) is discussed from B3LYP density functional theory calculations. The concerted OH group attack to the α-carbon by the iron−hydroperoxo species is investigated using a model with full protoporphyrin IX to confirm our previous conclusion that this species does not have sufficient oxidizing power for heme oxidation (J. Am. Chem. Soc. 2004, 126, 3672). Calculated activation energies and structures of the intermediates and transition state for this process remain unchanged from those for a small model with porphine in the previous study, which shows that the inclusion of the side chain of the porphyrin ring is not essential in describing the OH group transfer. The activation barrier for a direct oxo attack to the α-carbon by an iron−oxo model is calculated to be 49.8 kcal/mol, the barrier height of which looks very high for the enzymatic reaction under physiological conditions. This large activation energy is due to a highly bent porphyrin structure in the transition state. However, a bridging water molecule plays an important role in reducing the porphyrin distortion in the transition state, resulting in a remarkable decrease of the activation barrier to 13.9 kcal/mol. A whole-enzyme model with about 4000 atoms is constructed to elucidate functions of the protein environment in this enzymatic reaction using QM/MM calculations. The key water molecule is fixed in the protein environment to ensure the low-barrier and regioselective heme oxidation. A water-assisted oxo mechanism of heme oxidation by heme oxygenase is proposed from these calculational results

Enantioselective Alkylation by Binaphthyl Chiral Phase-Transfer Catalysts: A DFT-Based Conformational Analysis

A conformational search method based on the density functional theory (DFT) was successfully applied to explore a mechanism for the highly enantioselective alkylation by binaphthyl-modifed chiral phase-transfer catalysts. Key interactions that govern the enantioselectivity were analyzed. The computational results are encouraging for further application of the DFT-based conformational search toward the rational design of next-generation asymmetric phase transfer catalysts

Low-Mode Conformational Search Method with Semiempirical Quantum Mechanical Calculations: Application to Enantioselective Organocatalysis

A conformational search program for finding low-energy conformations of large noncovalent complexes has been developed. A quantitatively reliable semiempirical quantum mechanical PM6-DH+ method, which is able to accurately describe noncovalent interactions at a low computational cost, was employed in contrast to conventional conformational search programs in which molecular mechanical methods are usually adopted. Our approach is based on the low-mode method whereby an initial structure is perturbed along one of its low-mode eigenvectors to generate new conformations. This method was applied to determine the most stable conformation of transition state for enantioselective alkylation by the Maruoka and cinchona alkaloid catalysts and Hantzsch ester hydrogenation of imines by chiral phosphoric acid. Besides successfully reproducing the previously reported most stable DFT conformations, the conformational search with the semiempirical quantum mechanical calculations newly discovered a more stable conformation at a low computational cost

Participation of Multioxidants in the pH Dependence of the Reactivity of Ferrate(VI)

Alcohol oxidation by ferrate (FeO42-) in water is investigated from B3LYP density functional theory calculations in the framework of polarizable continuum model. The oxidizing power of three species, nonprotonated, monoprotonated, and diprotonated ferrates, was evaluated. The LUMO energy levels of nonprotonated and monoprotonated ferrates are greatly reduced by solvent effects, and as a result the oxidizing power of these two species is increased enough to effectively mediate a hydrogen-atom abstraction from the C−H and O−H bonds of methanol. The oxidizing power of these oxidants increases in the order nonprotonated ferrate < monoprotonated ferrate < diprotonated ferrate. The reaction pathway is initiated by C−H bond activation, followed by the formation of a hydroxymethyl radical intermediate or an organometallic intermediate with an Fe−C bond. Kinetic aspects of this reaction are analyzed from calculated energy profiles and experimentally known pKa values. The pH dependence of this reaction in water is explained well in terms of a multioxidant scheme

A Theoretical Study of the Dynamic Behavior of Alkane Hydroxylation by a Compound I Model of Cytochrome P450

Dynamic aspects of alkane hydroxylation mediated by Compound I of cytochrome P450 are discussed from classical trajectory calculations at the B3LYP level of density functional theory. The nuclei of the reacting system are propagated from a transition state to a reactant or product direction according to classical dynamics on a Born−Oppenheimer potential energy surface. Geometric and energetic changes in both low-spin doublet and high-spin quartet states are followed along the ethane to ethanol reaction pathway, which is partitioned into two chemical steps:  the first is the H-atom abstraction from ethane by the iron−oxo species of Compound I and the second is the rebound step in which the resultant iron−hydroxo complex and the ethyl radical intermediate react to form the ethanol complex. Molecular vibrations of the C−H bond being dissociated and the O−H bond being formed are significantly activated before and after the transition state, respectively, in the H-atom abstraction. The principal reaction coordinate that can represent the first chemical step is the C−H distance or the O−H distance while other geometric parameters remain almost unchanged. The rebound process begins with the iron−hydroxo complex and the ethyl radical intermediate and ends with the formation of the ethanol complex, the essential process in this reaction being the formation of the C−O bond. The H−O−Fe−C dihedral angle corresponds to the principal reaction coordinate for the rebound step. When sufficient kinetic energy is supplied to this rotational mode, the rebound process should efficiently take place. Trajectory calculations suggest that about 200 fs is required for the rebound process under specific initial conditions, in which a small amount of kinetic energy (0.1 kcal/mol) is supplied to the transition state exactly along the reaction coordinate. An important issue about which normal mode of vibration is activated during the hydroxylation reaction is investigated in detail from trajectory calculations. A large part of the kinetic energy is distributed to the C−H and O−H stretching modes before and after the transition state for the H-atom abstraction, respectively, and a small part of the kinetic energy is distributed to the Fe−O and Fe−S stretching modes and some characteristic modes of the porphyrin ring. The porphyrin marker modes of ν3 and ν4 that explicitly involve Fe−N stretching motion are effectively enhanced in the hydroxylation reaction. These vibrational modes of the porphyrin ring can play an important role in the energy transfer during the enzymatic process

Catalytic Roles of Active-Site Amino Acid Residues of Coenzyme B₁₂-Dependent Diol Dehydratase: Protonation State of Histidine and Pull Effect of Glutamate

The hydrogen abstraction and the OH migration processes catalyzed by diol dehydratase are discussed by means of a quantum mechanical/molecular mechanical method. To evaluate the push effect of His143 and the pull effect of Glu170, we considered three kinds of whole-enzyme model, the protonated and two unprotonated His143 models. A calculated activation energy for the hydrogen abstraction by the adenosyl radical is 15.6 (13.6) kcal/mol in the protonated (unprotonated) His143 model. QM/MM calculational results show that the mechanism of the OH migration is significantly changed by the protonation of His143. In the protonated His143 model, the OH group migration triggered by the full proton donation from the imidazolium to the migrating OH group occurs by a stepwise OH abstraction/re-addition process in which the water production reduces the barrier for the C−O bond cleavage. On the other hand, the OH migration in the unprotonated His143 model proceeds in a concerted manner, as we previously proposed using a simple model including only K+ ion and substrate. The latter mechanism seems to be kinetically more favorable from the calculated energy profiles and is consistent with experimental results. The activation barrier of the OH group migration step is only 1.6 kcal/mol reduced by the hydrogen-bonding interaction between the O2 of the substrate and unprotonated His143. Thus, it is predicted that His143 is not protonated, and therefore the main active-site amino acid residue that lowers the energy of the transition state for the OH group migration is determined to be Glu170

How Heme Metabolism Occurs in Heme Oxygenase: Computational Study of Oxygen-Donation Ability of the Oxo and Hydroperoxo Species

We report a density functional theory study on the heme metabolism in heme oxygenase using iron−hydroperoxo and −oxo models. The activation energies for heme oxidation at the α-carbon by the iron−hydroperoxo and −oxo species are calculated to be 42.9 and 39.9 kcal/mol, respectively. These high activation barriers lead us to reconsider the catalytic mechanism of heme oxygenas

Theoretical Study of the Direct Synthesis of H₂O₂ on Pd and Pd/Au Surfaces

The direct synthesis of hydrogen peroxide on Pd and Pd/Au catalysts was investigated with first-principle DFT methods for periodic two-dimensional surfaces. A two-step reaction mechanism was proposed starting from a superoxo precursor state of the dioxygen molecule on Pd surface and its subsequent reaction with two hydrogen atoms situated over neighboring 3-fold positions. A competitive reaction of dioxygen dissociation leading to the nonselective formation of water was found. We have shown that the presence of surface gold atoms blocks this dissociation and increases the selectivity toward the main product, H2O2, which explains the experimentally reported data

Inactivation Mechanism of Glycerol Dehydration by Diol Dehydratase from Combined Quantum Mechanical/Molecular Mechanical Calculations

Inactivation of diol dehydratase during the glycerol dehydration reaction is studied on the basis of quantum mechanical/molecular mechanical calculations. Glycerol is not a chiral compound but contains a prochiral carbon atom. Once it is bound to the active site, the enzyme adopts two binding conformations. One is predominantly responsible for the product-forming reaction (GR conformation), and the other primarily contributes to inactivation (GS conformation). Reactant radical is converted into a product and byproduct in the product-forming reaction and inactivation, respectively. The OH group migrates from C2 to C1 in the product-forming reaction, whereas the transfer of a hydrogen from the 3-OH group of glycerol to C1 takes place during the inactivation. The activation barrier of the hydrogen transfer does not depend on the substrate-binding conformation. On the other hand, the activation barrier of OH group migration is sensitive to conformation and is 4.5 kcal/mol lower in the GR conformation than in the GS conformation. In the OH group migration, Glu170 plays a critical role in stabilizing the reactant radical in the GS conformation. Moreover, the hydrogen bonding interaction between Ser301 and the 3-OH group of glycerol lowers the activation barrier in GR-TS2. As a result, the difference in energy between the hydrogen transfer and the OH group migration is reduced in the GS conformation, which shows that the inactivation is favored in the GS conformation

What is the Identity of the Metal Ions in the Active Sites of Coenzyme B₁₂-Dependent Diol Dehydratase? A Computational Mutation Analysis

What is the identity of the metal ion in the active sites of diol dehydratase? To address this question, we calculated the M−O bond lengths in the active sites using QM/MM calculations (M = K, Na, Mg, Ca). Our results show that the previous assignment of the metal ion in the substrate-binding site is wrong and that the identity of the metal ion is likely to be Ca2+. This is consistent with accumulated experimental evidence