The ONIOM Method and Its Applications

Chung, Lung Wa; Sameera, W. M. C.; Ramozzi, Romain; Page, Alister J.; Hatanaka, Miho; Петрова, Г. П.; Harris, Travis V.; Li, Xin; Ke, Zhuofeng; Liu, Fengyi; Li, Hai Bei; Ding, Ling; Morokuma, Keiji

doi:10.1021/cr5004419

Cited by 991 publications

(895 citation statements)

References 1,168 publications

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“…Chung et al (36), in their review of the method used here, note the challenging task to carry out stable geometry optimization of a complex system with an enormous number of degrees of freedom that leads to a great number of potential conformations. By necessity, our sampling is limited but, we believe in this case, is adequate for the current exploration.…”

Section: Discussionmentioning

confidence: 99%

Requirement for transient metal ions revealed through computational analysis for DNA polymerase going in reverse

Perera

Freudenthal

Beard

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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DNA polymerases facilitate faithful insertion of nucleotides, a central reaction occurring during DNA replication and repair. DNA synthesis (forward reaction) is "balanced," as dictated by the chemical equilibrium by the reverse reaction of pyrophosphorolysis. Two closely spaced divalent metal ions (catalytic and nucleotide-binding metals) provide the scaffold for these reactions. The catalytic metal lowers the pK a of O3′ of the growing primer terminus, and the nucleotide-binding metal facilitates substrate binding. Recent time-lapse crystallographic studies of DNA polymerases have identified an additional metal ion (product metal) associated with pyrophosphate formation, leading to the suggestion of its possible involvement in the reverse reaction. Here, we establish a rationale for a role of the product metal using quantum mechanical/molecular mechanical calculations of the reverse reaction in the confines of the DNA polymerase β active site. Additionally, site-directed mutagenesis identifies essential residues and metal-binding sites necessary for pyrophosphorolysis. The results indicate that the catalytic metal site must be occupied by a magnesium ion for pyrophosphorolysis to occur. Critically, the product metal site is occupied by a magnesium ion early in the pyrophosphorolysis reaction path but must be removed later. The proposed dynamic nature of the active site metal ions is consistent with crystallographic structures. The transition barrier for pyrophosphorolysis was estimated to be significantly higher than that for the forward reaction, consistent with kinetic activity measurements of the respective reactions. These observations provide a framework to understand how ions and active site changes could modulate the internal chemical equilibrium of a reaction that is central to genome stability.NA polymerases are responsible for high-fidelity DNA synthesis during replication and repair of the genome (1). Although there are at least 17 human DNA polymerases, they all use a general nucleotidyl transferase DNA synthesis reaction. This reaction requires deoxynucleoside triphosphates (dNTPs), divalent metal ions, and DNA substrate with a primer 3′-OH annealed to a coding template strand. An inline nucleophilic attack of the primer 3′-oxyanion on P α of the incoming dNTP results in products with DNA extended by one nucleotide [i.e., deoxynucleoside monophosphate (dNMP)] and pyrophosphate (PP i ). If the enzyme does not release PP i , pyrophosphorolysis (reverse reaction) can generate dNTP and a DNA strand that is one nucleotide shorter (Fig. 1) (2).Although the forward DNA synthesis reaction is preferred, the pyrophosphorolysis reaction can be biologically significant. Because DNA polymerases are an attractive chemotherapeutic target, chainterminating nucleoside drugs are often used in a strategy of blocking DNA synthesis (3-5). However, drug resistance to chain-terminating agents is influenced by the ability of a stalled DNA polymerase to remove chain-terminating nucleotides through pyrophosphorolysis (6-8)...

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Section: Discussionmentioning

confidence: 99%

Requirement for transient metal ions revealed through computational analysis for DNA polymerase going in reverse

Perera

Freudenthal

Beard

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…This technique provides a better description of the electrostatic interaction between the QM and MM regions than the mechanical embedding method and allows the QM wave function to be polarized by the MM environment. 47 Ten representative structures were selected from the wild-type MD simulation. All of these structures were optimized by QM/MM to decide the suitable starting structure for the subsequent potential energy scan ( Figure S5).…”

Section: Reaction Pathway Of Pmk By Qm/mm Studymentioning

confidence: 99%

Phosphorylation Mechanism of Phosphomevalonate Kinase: Implications for Rational Engineering of Isoprenoid Biosynthetic Pathway Enzymes

Huang

Wei

et al. 2016

J. Phys. Chem. B

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Mevalonate pathway is of important clinical, pharmaceutical and biotechnological relevance.However, lack of the understanding of the phosphorylation mechanism of the kinases in this pathway has limited rationally engineering the kinases in industry. Here the phosphorylation reaction mechanism of a representative kinase in the mevalonate pathway, phosphomevalonate kinase, was studied by using molecular dynamics and hybrid QM/MM methods. We find that a conserved residue (Ser106) is reorientated to anchor ATP via a stable H-bond interaction. In addition, Ser213 located on the α-helix at the catalytic site is repositioned to further approach the substrate, facilitating the proton transfer during the phosphorylation. Furthermore, we elucidate that Lys101 functions to neutralize the negative charge developed at the β-, γ-bridging oxygen atom of ATP during phosphoryl transfer. We demonstrate that the dissociative catalytic reaction occurs via a direct phosphorylation pathway. This is the first study on the phosphorylation mechanism of a mevalonate pathway kinase. The elucidation of the catalytic mechanism not only sheds light on the common catalytic mechanism of GHMP kinase superfamily, but also provides the structural basis for engineering the mevalonate pathway kinases to further exploit their applications in the production of a wide range of fine chemicals such as biofuels or pharmaceuticals.3

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“…Heavy atoms beyond this region were fixed to their crystallographic positions. In the prepared protein, the QM+RMM region, all added waters (but not crystal waters) and Na + ions, and all hydrogen atoms were first minimized, then annealed in a short molecular dynamics run, and minimized again to yield the final structure for the resting Geometry optimizations of the minima and transition states (TSs) were carried out using the mechanical embedding ONIOM method, 54 with part of the MM charges of the QM atoms iteratively updated, 55,56 using a quadratically convergent microiterative algorithm. 57 In these runs, only residues within 6.0 Å of the QM+RMM region were included (1008 optimized atoms, 4309 atoms in total for the resting state).…”

Section: Computational Detailsmentioning

confidence: 99%

Pathways for Arene Oxidation in Non-Heme Diiron Enzymes: Lessons from Computational Studies on Benzoyl Coenzyme A Epoxidase

Rokob

2016

J. Am. Chem. Soc.

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Oxygenation of aromatic rings using O2 is catalyzed by several non-heme carboxylate-bridged diiron enzymes. In order to provide a general mechanistic description for these reactions, computational studies were carried out at the ONIOM(B3LYP/BP86/Amber) level on the non-heme diiron enzyme benzoyl Specifically for the BoxB enzyme, the Q pathway was found to be the most preferred, but the corresponding bis(μ-oxo)-diiron(IV) species is significantly destabilized and not expected to be directly observable. Epoxidation via the Pσ* pathway represents an energetically somewhat higher lying alternative; possible strategies for experimental discrimination are discussed. The selectivity toward epoxidation is shown to stem from a combination of inherent electronic properties of the thioacyl substituent and enzymatic constraints. Possible implications of the results for toluene monooxygenases are considered as well.2

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The ONIOM Method and Its Applications

Cited by 991 publications

References 1,168 publications

Requirement for transient metal ions revealed through computational analysis for DNA polymerase going in reverse

Requirement for transient metal ions revealed through computational analysis for DNA polymerase going in reverse

Phosphorylation Mechanism of Phosphomevalonate Kinase: Implications for Rational Engineering of Isoprenoid Biosynthetic Pathway Enzymes

Pathways for Arene Oxidation in Non-Heme Diiron Enzymes: Lessons from Computational Studies on Benzoyl Coenzyme A Epoxidase

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