QM/MM studies of enzymes

Senn, Hans Martin; Thiel, Walter

doi:10.1016/j.cbpa.2007.01.684

Cited by 369 publications

(256 citation statements)

References 51 publications

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“…The geometry optimization of the PCB chromophore and binding site of Cph2 and Cph1 phytochromes, comprising all atoms within a 22-Å radius from the chromophore, were performed at the QM/MM level (29). Although the QM fragment, consisting of the PCB chromophore, the Cys 129 side chain, and the pyrrole water that is bound to rings A, B, and C nitrogens, were described with the B3LYP density functional (30), the remaining protein atoms as well as solvation waters with the CHARMM22 force field (31).…”

Section: Methodsmentioning

confidence: 99%

Structure of the Cyanobacterial Phytochrome 2 Photosensor Implies a Tryptophan Switch for Phytochrome Signaling

Anders

Daminelli-Widany

Mroginski

et al. 2013

Journal of Biological Chemistry

168

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Background: Phytochromes are red/far-red photoreceptors using a bilin chromophore. Results: Compared with Cph1, the Cph2 bilin-binding site differs around the propionates, but utilizes an otherwise conserved tongue for sealing the chromophore from solvent. Conclusion:The tongue signals via a tryptophan switch within the tongue-GAF domain interface. Significance: The first structure of a Cph2-type phytochrome indicates a common mechanism for photoswitching in all canonical phytochromes.

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Section: Methodsmentioning

confidence: 99%

Structure of the Cyanobacterial Phytochrome 2 Photosensor Implies a Tryptophan Switch for Phytochrome Signaling

Anders

Daminelli-Widany

Mroginski

et al. 2013

Journal of Biological Chemistry

168

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“…To probe this possibility, we used a quantum mechanical/molecular mechanical (QM/MM) computational approach (20,21) that has become an instrumental tool in mechanistic studies on enzyme catalysis. The results provide evidence that transient metal ions mediate charge distribution within the polymerase active site during chemistry that can alter the internal chemical equilibrium between the forward and reverse reactions.…”

Section: +mentioning

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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“…There exist a variety of approaches to describe that frontier bond, for example capping potentials [22,26], generalized hybrid orbitals [16] or localized self-consisted field [3,33,40], but the simplest, yet very accurate [2] and therefore also highly popular [27,36] method is hydrogen capping [39].…”

mentioning

confidence: 99%

Optimizing link atom parameters for DNA QM/MM simulations

et al. 2016

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utilize popular force fields like AMBER [9], CHARMM [8], OPLS [23] or GROMOS [35] is the ability to describe effects stemming from the intra-or intermolecular shifts of electron density for any desired chemical system. Due to this, phenomena such as charge transfers, the cleavage or formation of covalent bonds and polarization effects can be studied in-depth. Additionally, the influence of different spin states, Jahn Teller distortion and even electronic excitations can be investigated without having to resort to specifically tailored force fields.One of the major challenges for that kind of investigation is a proper description of the interface between the QM and the MM region, especially if covalent bonds are reaching through the boundary between the two regions [27]. There exist a variety of approaches to describe that frontier bond, for example capping potentials [22,26], generalized hybrid orbitals [16] or localized self-consisted field [3,33,40], but the simplest, yet very accurate [2] and therefore also highly popular [27,36] method is hydrogen capping [39].A big question regarding hydrogen-capping approaches is the proper placement of the inserted atom, so that its influence on the behavior of the surrounding atoms is minimized as much as possible. In a previous work [18], this was discussed in detail for amino acids, with the recommendation to use separate parameters for each type of sidechain to considerably improve the description of the link bond. In this work, the focus lies on the QM/MM separation of DNA nucleosides, with the C-N bond between the deoxyribose and the nucleobase acting as the link bond. Abstract This work optimizes the link bond description of the quantum mechanical/molecular mechanical separation of deoxynucleosides. The nucleosides are separated at the C-N bond between the nucleobase and the deoxyribose, with the former acting as the quantum mechanically described species. By using a flexible link atom-ansatz plus a harmonic potential to correct the energy deviation from a full quantum mechanical description, the potential energy well of the bond's stretching motion is mimicked with very high accuracy.

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QM/MM studies of enzymes

Cited by 369 publications

References 51 publications

Structure of the Cyanobacterial Phytochrome 2 Photosensor Implies a Tryptophan Switch for Phytochrome Signaling

Structure of the Cyanobacterial Phytochrome 2 Photosensor Implies a Tryptophan Switch for Phytochrome Signaling

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

Optimizing link atom parameters for DNA QM/MM simulations

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