A Generalized Hybrid Orbital (GHO) Method for the Treatment of Boundary Atoms in Combined QM/MM Calculations

Gao, Jiali; Amara, Patricia; Alhambra, Cristóbal; Field, Martin J.

doi:10.1021/jp9809890

Cited by 506 publications

(549 citation statements)

References 28 publications

(57 reference statements)

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“…The third category is the hybrid-orbital approach which employs either hybrid or localized frozen orbitals on the QM atom of the QM-MM covalent pair. 34,35 The link atom approach is by far the simplest to implement, and if used carefully can give satisfactory results. 36 A recent study by König et al on the effect of different QM/MM frontier treatments with SCC-DFTB as the QM method also concluded that the effect of using different link atom schemes in QM/MM simulations is rather small, especially in reactions that conserve the total charge, and emphasizes that other technical details such as the treatment of long-range electrostatics can often play a more important role.…”

Section: Qm/mmmentioning

confidence: 99%

Implementation of the SCC-DFTB Method for Hybrid QM/MM Simulations within the Amber Molecular Dynamics Package

et al. 2007

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Self-Consistent Charge Density Functional Tight Binding (SCC-DFTB) is a semi-empirical method based on Density Functional Theory, and has in many cases been shown to provide relative energies and geometries comparable in accuracy to full DFT or ab-initio MP2 calculations using large basis sets. This article shows an implementation of the SCC-DFTB method as part of the new QM/MM support in the AMBER 9 molecular dynamics program suite. Details of the implementation and examples of applications are shown.

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Section: Qm/mmmentioning

confidence: 99%

Implementation of the SCC-DFTB Method for Hybrid QM/MM Simulations within the Amber Molecular Dynamics Package

et al. 2007

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“…The entire chemical system was divided into a QM region, treated by the AM1 semiempirical MO method, and a MM region comprising the rest of the protein (CHARMM26 potentials) 11 and the water molecules. The generalized hybrid orbital (GHO) 12 method was used to treat those covalent bonds crossing the boundary between the QM and the MM regions. The QM region, formed by the dihydronicotinamide and the ribose ring of the NADH, Arg171, Arg109, the pyruvate and the His195 contained a total of 78 atoms.…”

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confidence: 99%

Dependence of enzyme reaction mechanism on protonation state of titratable residues and QM level description: lactate dehydrogenase

et al. 2005

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We have studied the dependence of the chemical reaction mechanism of L-lactate dehydrogenase (LDH) on the protonation state of titratable residues and on the level of the quantum mechanical (QM) description by means of hybrid quantum-mechanical/molecular-mechanical (QM/MM) methods; this methodology has allowed clarification of the timing of the hydride transfer and proton transfer components that hitherto had not been possible to state definitively.It is observed macroscopically that proteins become unstable at extreme values of pH, but properties of enzymes are also pH dependent because their efficacy depends on the protonation state of their ionisable residues. The most expensive computational simulation may give meaningless results if an erroneous charge is selected for a single amino acid of the protein. Thus any theoretical analysis of protein structure or reactivity requires an adequate titration of all ionisable residues. Assignment of the protonation states of such residues is often based on the pK a of the corresponding amino acids in aqueous solution. However, this practice may introduce significant artefacts into simulations because standard pK a values of ionisable groups are shifted by local protein environments. 1 LDH is a highly stereospecific metabolic enzyme that catalyses the interconversion of pyruvate and lactate using the NADH/ NAD + pair as redox cofactor. This chemical step involves a hydride transfer (HT) from the dihydronicotinamide ring of NADH to the carbonyl C atom of pyruvate and a proton transfer (PT) to the carbonyl O atom from a N atom of the protonated His195 residue (Scheme 1).Although the rate-limiting step of the full catalytic process in the wild-type enzyme is a conformational change involving closure of a surface loop (99-110) down over the active site, 2 nonetheless the chemical step catalyzed by LDH has been extensively studied both experimentally 3 and theoretically. [4][5][6][7][8] Although the relative timing of the HT and PT components is a matter of interest in mechanistic enzymology, it is not yet possible to state definitively which mechanism is preferred. 8 While a stepwise mechanism is more likely than a concerted one, results from various computational groups differ in the order in which the HT and PT steps occur. [4][5][6][7][8] Initially the oxamate inhibitor in the ternary complex X-ray crystal structure 9 of LDH tetramer from B. stearothermophilus with NADH cofactor was replaced by pyruvate. To assign protonation states for acidic and basic residues, two alternative strategies were considered. In the first, all ionisable groups were set at a state complementary to pH 7 using the pK a values of the amino acids in aqueous solution, with the exception of His195, which was modelled in its doubly protonated form.The second protocol involved recalculation of the pK a values using the ''cluster method'', 1 as implemented by Field and coworkers, 10 according to which each titratable residue in the protein is perturbed by the electrostatic effect of the protein env...

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“…As mentioned above, the link atom scheme has been the most popular with semiempirical QM/MM potentials, although other algorithms have been proposed. These include methods based upon hybrid orbitals 51,55,56 and those that use pseudoatoms. 57 Although these methods are more elegant in that they dispense with the fictitious link atoms in the QM region, they have not yet been shown to be consistently better than the newer link atom approximations, 58,59 which are more versatile and, in comparison to the hybrid orbital methods, simpler to implement.…”

Section: Hybrid Potential Methodsmentioning

confidence: 99%

Simulating enzyme reactions: Challenges and perspectives

2001

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Elucidating how enzymes enhance the rates of the reactions that they catalyze is a major goal of contemporary biochemistry, and it is an area in which computational and theoretical techniques can make a major contribution. This article outlines some of the processes that need to be investigated if enzyme catalysis is to be understood, reviews the current state-of-the-art in enzyme simulation work, and highlights challenges for the future.

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A Generalized Hybrid Orbital (GHO) Method for the Treatment of Boundary Atoms in Combined QM/MM Calculations

Cited by 506 publications

References 28 publications

Implementation of the SCC-DFTB Method for Hybrid QM/MM Simulations within the Amber Molecular Dynamics Package

Implementation of the SCC-DFTB Method for Hybrid QM/MM Simulations within the Amber Molecular Dynamics Package

Dependence of enzyme reaction mechanism on protonation state of titratable residues and QM level description: lactate dehydrogenase

Simulating enzyme reactions: Challenges and perspectives

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