Combining Quantum Mechanics Methods with Molecular Mechanics Methods in ONIOM

Vreven, Thom; Byun, K. Suzie; Komáromi, István; Dapprich, Stefan; Montgomery, John A.; Morokuma, Keiji; Frisch, Michael J.

doi:10.1021/ct050289g

Cited by 886 publications

(835 citation statements)

References 40 publications

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“…32 The electrostatic interaction between the QM and MM regions were optimized by using electronic embedding, which incorporates the partial charges of the MM region into the quantum mechanical Hamiltonian and allows the QM wavefunction to be polarised. 36 MerzKollman-Singh approximate charge was used during optimization microiterations with electronic embedding. 37,38 The QM region included ATP, PMV, Ala293, Asp297, Lys9, Lys101, Ser213 and three water molecules that were coordinated to the Mg ion ( Figure 1).…”

Section: Qm/mm Calculationsmentioning

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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Section: Qm/mm Calculationsmentioning

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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“…[5][6][7][8] In the present QM:MM model, the metal center, i.e., iron, iron ligands and substrate, is treated by density-functional theory (DFT), while the rest of the enzyme is treated by a classical force field. The two-layer approach is not only computationally efficient, but also makes it easier to separate effects from the metal center from those of the surrounding protein because they are described at different computational levels.…”

Section: Introductionmentioning

confidence: 99%

Transition States in a Protein Environment − ONIOM QM:MM Modeling of Isopenicillin N Synthesis

Lundberg

Kawatsu

Vreven

et al. 2008

J. Chem. Theory Comput.

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117

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Abstract.To highlight the role of the protein in metal enzyme catalysis, we optimize ONIOM QM:MM transition states and intermediates for the full reaction of the non-heme iron enzyme isopenicillin N synthase (IPNS). Optimizations of transition states in large protein systems are possible using our new geometry optimizer with quadratic coupling between the QM and MM regions. [Vreven, T. et. al., Mol. Phys. 2006, 104, 701-704]. To highlight the effect of the metal center, results from the protein model are compared to results from an active site model containing only the metal center and coordinating residues [Lundberg, M. et. al., Biochemistry 2008, 47, 1031-1042. The analysis suggests that the main catalytic effect comes from the metal center, while the protein controls the reactivity to achieve high product specificity. As an example, hydrophobic residues align the valine substrate radical in a favorable conformation for thiazolidine ring closure and contribute to product selectivity and high stereospecificity.

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“…In this work we investigate an alternative to the traditional approaches, which is to apply a hybrid method: Our own N-layer integrated molecular orbital molecular mechanics ͑ONIOM͒. [10][11][12][13][14][15][16][17][18] Hybrid methods divide the system into regions and treat each with a different level of theory. By only using expensive methods for the part of the system where it is necessary, hybrid methods allow the accurate study of the chemistry of very large systems.…”

Section: Introductionmentioning

confidence: 99%

Using the ONIOM hybrid method to apply equation of motion CCSD to larger systems: Benchmarking and comparison with time-dependent density functional theory, configuration interaction singles, and time-dependent Hartree–Fock

Caricato

Vreven

Trucks

et al. 2009

The Journal of Chemical Physics

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Assessment of time-dependent density functional schemes for computing the oscillator strengths of benzene, phenol, aniline, and fluorobenzene J. Chem. Phys. 127, 084103 (2007) Equation of motion coupled-cluster singles and doubles ͑EOM-CCSD͒ is one of the most accurate computational methods for the description of one-electron vertical transitions. However, its O͑N 6 ͒ scaling, where N is the number of basis functions, often makes the study of molecules larger than 10-15 heavy atoms prohibitive. In this work we investigate how accurately less expensive methods can approximate the EOM-CCSD results. We focus on our own N-layer integrated molecular orbital molecular mechanics ͑ONIOM͒ hybrid scheme, where the system is partitioned into regions which are treated with different levels of theory. For our set of benchmark calculations, the comparison of conventional configuration interaction singles ͑CIS͒, time-dependent Hartree-Fock ͑TDHF͒, and time-dependent density functional theory ͑TDDFT͒ methods and ONIOM ͑with different low level methods͒ showed that the best accuracy-computational time combination is obtained with ONIOM͑EOM:TDDFT͒, which has a rms of the error with respect to the conventional EOM-CCSD of 0.06 eV, compared with 0.47 eV of the conventional TDDFT.

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Combining Quantum Mechanics Methods with Molecular Mechanics Methods in ONIOM

Cited by 886 publications

References 40 publications

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

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

Transition States in a Protein Environment − ONIOM QM:MM Modeling of Isopenicillin N Synthesis

Using the ONIOM hybrid method to apply equation of motion CCSD to larger systems: Benchmarking and comparison with time-dependent density functional theory, configuration interaction singles, and time-dependent Hartree–Fock

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