Coupled semiempirical molecular orbital and molecular mechanics model (QM/MM) for organic molecules in aqueous solution

Cummins, Peter L.; Gready, Jill E.

doi:10.1002/(sici)1096-987x(199709)18:12<1496::aid-jcc7>3.0.co;2-e

Cited by 66 publications

(66 citation statements)

References 52 publications

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“…We recently reported results of both quantum chemical calculations and MD simulations within a QM/MM scheme for both the substrate and activesite residue protonations. [9][10][11] These studies demonstrated the importance of the conserved water molecule, corresponding to W206 in the E. coli DHFR complexes (Figure 1), and also suggested that the issue of OD2 protonation is likely to be important mechanistically. 11 Overall, these results tended to support a mechanism for both folate and DHF reductions in which the OD2 carboxyl oxygen is first protonated, followed by a direct protonation at N8 (folate) or N5 (DHF) to obtain the doubly protonated active cation complexes.…”

Section: Introductionmentioning

confidence: 84%

Computational Methods for the Study of Enzymic Reaction Mechanisms. 1. Application to the Hydride Transfer Step in the Catalysis of Dihydrofolate Reductase

et al. 2002

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We report results and assessment from the use of several "state-of-the-art" computational methods to investigate the effect of the Asp27 ionization state on the hydride-ion transfer step in the enzymic reduction of folate and dihydrofolate (DHF) by DHFR from Escherichia coli (E. coli). The active forms of the DHFR complex are assumed protonated on the pterin/dihydropterin ring of the folate/dihydrofolate molecule prior to transfer of the hydride ion from the nicotinamide adenine dinucleotide phosphate (NADPH) cofactor. The calculations have been carried out for both protonated (neutral) and unprotonated (negatively charged) states of the conserved active-site Asp27 (E. coli) residue in the DHFR complexes. First, geometry optimizations at the semiempirical (PM3), density functional (DFT) and ab initio levels were performed on reaction-analogue clusters to obtain reactant, transition state (TS), and product complexes. The DFT and ab initio reaction energies obtained for the unprotonated Asp complexes were endothermic: exothermic reaction energies were obtained only for the protonated Asp complexes. In contrast, the PM3 method wrongly predicted endothermic reactions for both unprotonated and protonated Asp. Thus, for these simple analogue systems, the results suggest that reduction takes place only if the active-site Asp27 is protonated. Second, the effects of the remaining substrate, cofactor, protein and solvent interactions were studied using hybrid semiempirical (PM3) quantum mechanical and molecular mechanics (QM/MM) methods combined with molecular dynamics (MD) simulations. Within the MD simulation scheme, TS complexes were characterized using an efficient implementation of the coordinatedriving technique. Errors arising from the use of PM3 in the QM/MM calculations were estimated and corrected using the results of additional cluster calculations at the DFT and MP2 levels. Contrary to the initial cluster calculations, these corrected QM/MM calculations did not indicate unambiguously that reduction takes place only if the active-site Asp27 is protonated. For both ionized and neutral states of Asp27, analysis of the electrostatic interaction energies between the QM and MM regions in the MD simulations showed that the enzymic environment (MM region) plays a far greater role in stabilizing the final products than in stabilizing the TS complex. Activation free energies for the hydride-ion transfer ranged from 10 to 30 kcal/mol depending on the choice of QM region and ionization state of Asp27. For the larger QM region, the range of activation free energies (10s12 kcal/mol) is similar to an experimental value (13 kcal/mol), but in general quantitative agreement with experimental free energies was poor. Comparative estimates of reaction free energies suggest the catalytic advantage of a protonated Asp27 residue is small. Methodologically, the present work has identified issues relating to the composition and semiempirical (PM3) treatment of the QM region which need to be addressed in future studies.

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Section: Introductionmentioning

confidence: 84%

Computational Methods for the Study of Enzymic Reaction Mechanisms. 1. Application to the Hydride Transfer Step in the Catalysis of Dihydrofolate Reductase

et al. 2002

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“…Only this approach suggests a consistent prescription for separating the inertial response field component at a molecular level. 43,44 Several other combined ͑hybrid͒ methods were suggested in the literature and, with a relevant parametrization, successfully used for the computation of hydration free energies of organic molecules 26,30,[45][46][47][48] and polyatomic ions. 25,27,30,31,49 All these methods are inapplicable for separating the inertial response.…”

Section: Discussionmentioning

confidence: 99%

Computations of solvation free energies for polyatomic ions in water in terms of a combined molecular–continuum approach

Vener

Leontyev

Basilevsky

2003

The Journal of Chemical Physics

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A new definition of cavities for the computation of solvation free energies by the polarizable continuum modelThe combined molecular-continuum approach developed in the preceding paper was applied for calculations of equilibrium solvation energies for a large number of polyatomic ions. The structure and charge distribution of the given ion were computed using the restricted Hartree-Fock level with the 6-31G** basis set. The standard Lennard-Jones ͑LJ͒ parameters, which were not specially calibrated to fit the solvation energies, were used in molecular dynamics simulations. Water ͑the SPC model͒ was considered as a solvent. The computations show that the new scheme works satisfactorily for nitrogen cations in the frame of a standard parametrization and can be further improved for oxygen ions by tuning solute-solvent LJ parameters. The calculated relative change of the energies in families of similar cations-i.e., ammonium-type or oxonium-type cations-fits the experimental trends. The present approach is specially addressed to separate the inertial contribution to solvation free energies, which is important in view of further applications to electron transfer reactions. Computed values of the inertial contribution to solvation energies of the ions and reorganization energies for the model two-site dumbbell system are found to be systematically lower than those obtained in terms of the standard treatments ͑using the Pekar factor or the polarizable continuum model ͑PCM͒͒.

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“…The basic approach is to treat the chemically most relevant region by quantum mechanics, whereas the rest of the system is treated by classical molecular a͒ Author to whom all correspondence should be addressed; electronic mail: bernd.m.rode@uibk.ac.at mechanics. [33][34][35][36][37][38][39][40][41] Such ab initio QM/MM molecular dynamics have been successfully employed for revealing structural and dynamic properties of various ions in solution. [42][43][44][45][46][47][48][49] In the present work the same way has been followed for the investigation of Hg 2ϩ , which in contrast to previously investigated metal ions represents the rather ''heavy'' elements and, therefore, also displays a quite different chemical behavior.…”

Section: Introductionmentioning

confidence: 99%

Molecular dynamics simulations of Hg2+ in aqueous solution including N-body effects

Kritayakornupong

Rode

2003

The Journal of Chemical Physics

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Articles you may be interested inThe structure of CaCl 2 aqueous solutions over a wide range of concentration. Interpretation of diffraction experiments via molecular simulation Structural and dynamical properties of Co(III) in aqueous solution: Ab initio quantum mechanical/molecular mechanical molecular dynamics simulation A study of aqueous solutions of lanthanide ions by molecular dynamics simulation with ab initio effective pair potentials Pair-potential, three-body corrected and combined ab initio quantum mechanics/molecular mechanics molecular dynamics ͑QM/MM-MD͒ simulations have been performed for Hg 2ϩ in water. The ion's hydration structure was evaluated in terms of radial distribution functions, coordination numbers, and angular distributions, together with changes in ligand structure upon binding of water molecules. An octahedral solvate complex with coordination number of 6/22 for first/second shell results from QM/MM-MD simulations, with average Hg 2ϩ -O distance 2.42 Å for the first shell. The pair-potential simulation gives strongly wrong results, the inclusion of three-body effects corrects many, but not all of the errors. The hydration enthalpy of Ϫ553Ϯ3 kcal/mol obtained from the QM/MM-MD simulation seems a reasonable value for dilute solution, when compared with experimental estimations.

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Coupled semiempirical molecular orbital and molecular mechanics model (QM/MM) for organic molecules in aqueous solution

Cited by 66 publications

References 52 publications

Computational Methods for the Study of Enzymic Reaction Mechanisms. 1. Application to the Hydride Transfer Step in the Catalysis of Dihydrofolate Reductase

Computational Methods for the Study of Enzymic Reaction Mechanisms. 1. Application to the Hydride Transfer Step in the Catalysis of Dihydrofolate Reductase

Computations of solvation free energies for polyatomic ions in water in terms of a combined molecular–continuum approach

Molecular dynamics simulations of Hg2+ in aqueous solution including N-body effects

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