Computational Insights into the Catalysis of the pH Dependence of Bromite Decomposition Catalyzed by Chlorite Dismutase from <i>Dechloromonas aromatica</i> (<i>Da</i>Cld)

The heme-containing chlorite dismutases catalyze the rapid and efficient decomposition of chlorite (ClO2–) to yield Cl– and O2, and the catalytic efficiency of chlorite dismutase from Dechloromonas aromatica (DaCld) in catalyzing the decomposition of bromite (BrO2–) was dependent on pH, which was supposed to be caused by the conversion of active Cpd I to the inactive Cpd II by proton-coupled electron transfer (PCET) from the pocket Tyr118 to the propionate side chain of heme at high pH. However, the direct evidence of PCET and how the pH affects the efficiency of DaCld, as well as whether Cpd II is really inactive, are still poorly understood. Here, on the basis of the high-resolution crystal structures, the computational models in both acidic (pH 5.0) and alkaline (pH 9.0) environments were constructed, and a series of quantum mechanical/molecular mechanical calculations were performed. On the basis of our calculation results, the O–Br bond cleavage of BrO2– always follows the homolytic mode to generate Cpd II rather than Cpd I. It is different from the O–O cleavage of O2/H2O2 or peracetic acid catalyzed by the other heme-containing enzymes. Thus, in the subsequent O–O rebound reaction, it is the Fe(IV)O in Cpd II that combines with the O–Br radical. Because the porphyrin ring in Cpd II does not bear an unpaired electron, the previously suggested PCET from Tyr118 to the propionate side chain of heme was not theoretically recognized in an alkaline environment. In addition, the O–O rebound step in an alkaline solution corresponds to an energy barrier that is larger than that in an acidic environment, which can well explain the pH dependence of the activity of DaCld. In addition, the protonation state of the propionic acid side chains of heme and the surrounding hydrogen bond networks were calculated to have a significant impact on the barriers of the O–O rebound step, which is mainly achieved by affecting the reactivity of the Fe(IV)O group in Cpd II. In an acidic environment, the relatively weaker coordination of the O2 atom to Fe leads to its higher reactivity toward the O–O rebound reaction. These observations may provide useful information for understanding the catalysis of chlorite dismutases

Theoretical Study of the Catalytic Mechanism of E1 Subunit of Pyruvate Dehydrogenase Multienzyme Complex from <i>Bacillus stearothermophilus</i>

Pyruvate dehydrogenase multienzyme complex (PDHc) is a member of a family of 2-oxo acid dehydrogenase (OADH) multienzyme complexes involved in several central points of oxidative metabolism, and the E1 subunit is the most important component in the entire PDHc catalytic system, which catalyzes the reversible transfer of an acetyl group from a pyruvate to the lipoyl group of E2 subunit lipoly domain. In this article, the catalytic mechanism of the E1 subunit has been systematically studied using density functional theory (DFT). Four possible pathways with different general acid/base catalysts in decarboxylation and reductive acylation processes were explored. Our calculation results indicate that the 4′-amino pyrimidine of ThDP and residue His128 are the most likely proton donors in the decarboxylation and reductive acylation processes, respectively. During the reaction, each C–C and C–S bond formation or cleavage process, except for the liberation of CO₂, is always accompanied by a proton transfer between the substrates and proton donors. The liberation of CO₂ is calculated to be the rate-limiting step for the overall reaction, with an energy barrier of 13.57 kcal/mol. The decarboxylation process is endothermic by 5.32 kcal/mol, whereas the reductive acylation process is exothermic with a value of 5.74 kcal/mol. The assignment of protonation states of the surrounding residues can greatly influence the reaction. Residues His128 and His271 play roles in positioning the first substrate pyruvate and second substrate lipoyl group, respectively

Tunable Electronic and Magnetic Properties of Transition Metal-Cyclopentadiene Sandwich Molecule Wires Functionalized Narrow Single Wall Carbon Nanotubes

The structural, electronic, and magnetic properties of 1D organometallic molecule wires functionalized narrow single wall carbon nanotube, [TMCp]_∞/SWCNTs (TM = Sc, V, Mn, Fe, Co, SWCNTs, (<i>n</i>, <i>m</i>) = (7,7), (10,0), (11,0)), are first studied by density functional theory calculations. In the case of the 1D [TMCp]_∞ wires encapsulated in SWCNTs, the reaction between 1D [TMCp]_∞ and SWCNTs are endothermic or exothermic depending on the diameters of SWCNTs, while the dimension confinement effect disappears through placing the organometallic molecular wires outside the SWCNTs. Moreover, obvious ionic bonding nature is identified in the systems by putting the 1D [TMCp]_∞ wire in or outside of the SWCNTs. In contrast, stronger covalent bonding nature is found for the derivatives by desorption of one raw of hydrogen atoms in the cyclopentadiene ligands. In particular, diverse electronic and magnetic properties are introduced by the choice of SWCNTs and the functionalized 1D [TMCp]_∞ wires, which allows the 1D [TMCp]_∞/SWCNTs wires to function as a basic building block for potential application in electronic- and spintronic-based devices

Ring Contraction Catalyzed by the Metal-Dependent Radical SAM Enzyme: 7‑Carboxy-7-deazaguanine Synthase from <i>B. multivorans</i>. Theoretical Insights into the Reaction Mechanism and the Influence of Metal Ions

7-Carboxy-7-deazaguanine synthase (QueE) is a radical <i>S</i>-adenosylmethionine (SAM) enzyme that catalyzes the conversion of 6-carboxy-5,6,7,8-tetrahydropterin (CPH₄) to 7-carboxy-7-deazaguanine (CDG). QueE also shows a clear dependence on Mg²⁺ ion and is considered a new feature for a radical SAM enzyme. The catalytic mechanism of QueE from <i>B. multivorans</i> has been studied using a combined quantum mechanics and molecular mechanics (QM/MM) method. The results of our calculations reveal that the key ring-contraction step involves a bridged intermediate rather than a ring-opening one. For the QueE–Mg²⁺ system, the elimination of ammonia is calculated to be rate limiting with a free energy barrier of 18.8 kcal/mol, which is basically in accordance with the estimated value (20.9 kcal/mol) from the experiment. For QueE–Na⁺ complex, the rate-limiting step switches to the formation of the bridged intermediate with an energy barrier of 29.3 kcal/mol. Natural population analysis indicates that the metal ions do not act as Lewis acids; therefore, they mainly play a role in fixing the substrate in its reactive conformation. The different coordination of Mg²⁺ and Na⁺ with the substrate is suggested to be the main reason for leading to the different activities of QueE–Mg²⁺ and QueE–Na⁺ complexes

Quantum Mechanics and Molecular Mechanics Study of the Catalytic Mechanism of Human AMSH-LP Domain Deubiquitinating Enzymes

Deubiquitinating enzymes (DUBs) catalyze the cleavage of the isopeptide bond in polyubiquitin chains to control and regulate the deubiquitination process in all known eukaryotic cells. The human AMSH-LP DUB domain specifically cleaves the isopeptide bonds in the Lys63-linked polyubiquitin chains. In this article, the catalytic mechanism of AMSH-LP has been studied using a combined quantum mechanics and molecular mechanics method. Two possible hydrolysis processes (Path 1 and Path 2) have been considered. Our calculation results reveal that the activation of Zn²⁺-coordinated water molecule is the essential step for the hydrolysis of isopeptide bond. In Path 1, the generated hydroxyl first attacks the carbonyl group of Gly76, and then the amino group of Lys63 is protonated, which is calculated to be the rate limiting step with an energy barrier of 13.1 kcal/mol. The energy barrier of the rate limiting step and the structures of intermediate and product are in agreement with the experimental results. In Path 2, the protonation of amino group of Lys63 is prior to the nucleophilic attack of activated hydroxyl. The two proton transfer processes in Path 2 correspond to comparable overall barriers (33.4 and 36.1 kcal/mol), which are very high for an enzymatic reaction. Thus, Path 2 can be ruled out. During the reaction, Glu292 acts as a proton transfer mediator, and Ser357 mainly plays a role in stabilizing the negative charge of Gly76. Besides acting as a Lewis acid, Zn²⁺ also influences the reaction by coordinating to the reaction substrates (W1 and Gly76)

Ab Initio Study of Structural, Electronic, and Magnetic Properties of Transition Metal Atoms Intercalated AA-Stacked Bilayer Graphene

The structural, electronic, and magnetic properties of transition metal atoms intercalated bilayer graphene, [GTMG]_{<i>x</i>/<i>y</i>}, (<i>x</i>, <i>y</i> is integer, TM = Ti, Cr, Mn, Fe) with different TM/carbon hexagons ratios and insertion patterns, are systematically studied by density functional theory calculations. All the studied systems are thermodynamically stable and competitive ionic–covalent bonding characters are dominated in the TM–graphene interaction. Most studied systems are ferromagnetic; particularly, [GCrG]_1:18, [GCrG]_1:9, [GFeG]_1:6(1), and [GTMG]_1:6(2) (TM = Cr, Mn, Fe) exhibit large magnetic moment of 4.43, 5.60, 7.02, 10.85, 9.04, and 5.19 μ_B per unit cell, respectively. In contrast, [GCrG]_1:8 and [GFeG]_1:8 are ferrimagnetic, while eight other [GTMG]_{<i>x</i>/<i>y</i>} are nonmagnetic. Moreover, five intercalation nanostructures of [GTMG]_1:18 (TM = Ti, Mn), [GTMG]_1:9 (TM = Ti, Mn) and [GTiG]_1:6 are semiconductors with the gaps of 0.141/0.824 eV, 0.413/0.668 eV, and 0.087 eV, respectively. Comparison on different isomers with same TM/carbon hexagons ratios showed that the electronic and magnetic properties of these [GTMG]_{<i>x</i>/<i>y</i>} are largely dependent on the TM atoms arrangement. For thus, an effective way to control the electronic and magnetic properties of graphene based nanostructures is proposed

Mechanism of Sulfoxidation and C–S Bond Formation Involved in the Biosynthesis of Ergothioneine Catalyzed by Ergothioneine Synthase (EgtB)

Ergothioneine synthase (EgtB) is a unique non-heme mononuclear iron enzyme that catalyzes the sulfoxidation and C–S bond formation between γ-glutamyl cysteine (γGC) and <i>N</i>-α-trimethyl histidine (TMH) as a pivotal step in the ergothioneine biosynthesis. A controversy has arisen regarding the sequence of sulfoxidation and C–S bond formation in the catalytic cycle. To clarify this issue, the QM/MM approach has been employed to investigate the detailed mechanism of EgtB. Two binding modes of O₂ to Fe­(II) (“end-on” and “side-on”) have been identified. Within the present computational model, the end-on binding mode of O₂ is preferred. The open-shell singlet is calculated to be the ground state, whereas the quintet is the most active state. Moreover, the sulfoxidation is prior to the formation of the C–S bond, and the reaction mainly occurs on the quintet state surface. Due to the electron transfer from the γGC to the ferric superoxide, the sulfur atom of γGC has partial radical characteristics, which facilitates the attack of the distal oxygen atom on the sulfur radical of γGC to form the sulfoxide. The formation of TMH C2 anion, i.e., the abstraction of the proton from the imidazole group in TMH by the Fe­(IV)–oxo species, is the prerequisite for C–S bond formation, which is the rate-limiting step with an energy barrier of 21.7 kcal/mol. In addition, it is also found that although the resulting iron­(III)–oxo can easily abstract a proton from Tyr377 to generate a phenolic hydroxyl anion, the subsequent proton transfer from C2 to Tyr377 is calculated to be difficult; thus, Tyr377 is not directly involved in the sulfoxidation and C–S bond formation. Our calculations also reveal that the side-on mode is not the catalytically relevant species. This work provides a direct comparison with previous experimental and theoretical studies, which is helpful for understanding the catalysis of ergothioneine synthase and related enzymes

Mechanism of the Glutathione Persulfide Oxidation Process Catalyzed by Ethylmalonic Encephalopathy Protein 1

Ethylmalonic encephalopathy protein 1 (ETHE1) is a β-lactamase fold-containing protein, which is related to the increased cellular levels of hydrogen sulfide. ETHE1 is essential for the survival of a range of organisms and catalyzes the oxidation of glutathione persulfide (GSSH). Currently, the catalytic mechanism of ETHE1 still remains unclear, despite a catalytic cycle that has been suggested from the crystal structure and a proposal for the mechanistically related cysteine dioxygenase (CDO). In this Article, we performed a series of quantum mechanical/molecular mechanical (QM/MM) calculations on the substrate GSSH oxidation by human ETHE1. Our calculation results reveal that the ground state of the iron­(II)-superoxo reactant is quintet, which can be described as GSS^+•–Fe­(II)–O₂^•, and the most feasible reaction channel was found to start from the cleavage of dioxygen and a concerted attack of distal oxygen on the sulfur atom of the substrate, forming the metal-bound activated oxygen and a sulfite intermediate. Moreover, the reaction starts from a quintet ground-state reactant, undergoes a triplet intermediate, and finally generates the septet product rather than the reaction of CDO, which starts from a singlet–quintet crossing

Water-Dependent Reaction Pathways: An Essential Factor for the Catalysis in HEPD Enzyme

The hydroxyethylphosphonate dioxygenase (HEPD) catalyzes the critical carbon–carbon bond cleavage step in the phosphinothricin (PT) biosynthetic pathway. The experimental research suggests that water molecules play an important role in the catalytic reaction process of HEPD. This work proposes a water involved reaction mechanism where water molecules serve as an oxygen source in the generation of mononuclear nonheme iron oxo complexes. These molecules can take part in the catalytic cycle before the carbon–carbon bond cleavage process. The properties of trapped water molecules are also discussed. Meanwhile, water molecules seem to be responsible for converting the reactive hydroxyl radical group (⁻OH) to the ferric hydroxide (Fe­(III)–OH) in a specific way. This converting reaction may prevent the enzyme from damages caused by the hydroxyl radical groups. So, water molecules may serve as biological catalysts just like the work in the heme enzyme P450 StaP. This work could provide a better interpretation on how the intermediates interact with water molecules and a further understanding on the O¹⁸ label experimental evidence in which only a relatively smaller ratio of oxygen atoms in water molecules (∼40%) are incorporated into the final product HMP

Tunable Electronic and Magnetic Properties of Boron/Nitrogen-Doped BzTMCp*TMBz/CpTMCp*TMCp Clusters and One-Dimensional Infinite Molecular Wires

We systematically studied the structural, electronic, and magnetic properties of B/N-doped BzTMCp*TMBz/CpTMCp*TMCp (Bz = C₆H₆; Cp = C₅H₅; Cp* = C_5–<i>x</i>D_<i>x</i>H₅; D = B, N; <i>x</i> = 1, 2; TM = V, Cr, Mn, Fe) sandwich clusters and their infinite molecular wires using first-principle calculations. It is found that the B/N-doped ligands do not degrade the linear stacked sandwich configurations compared with the pristine hydrocarbon ligand complexes. Different from the N-doped complexes, the B-doped ligands lead to more charge transfers from metal atoms, and such behavior allows for the enhanced structure stabilities and adds the advantage of electronic and magnetic properties manipulation. Moreover, the B-doped ligand makes the one-dimensional sandwich molecular wires conserve half metallic properties of the pristine molecular wires, undergo half metal–semiconductor transition, and vice versa. Thus, a novel strategy for efficient tailoring of the electronic and magnetic properties of metal–ligand sandwich complexes is presented