| 51. |
- Srnec, Martin, et al.
(författare)
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Reaction Mechanism of Manganese Superoxide Dismutase Studied by Combined Quantum and Molecular Mechanical Calculations and Multiconfigurational Methods.
- 2009
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Ingår i: The Journal of Physical Chemistry Part B. - : American Chemical Society (ACS). - 1520-5207 .- 1520-6106. ; 113:17, s. 6074-6086
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Tidskriftsartikel (refereegranskat)abstract
- Manganese superoxide dismutases (MnSODs) are enzymes that convert two molecules of the poisonous superoxide radical into molecular oxygen and hydrogen peroxide. During the reaction, the manganese ion cycles between the Mn(2+) and Mn(3+) oxidation states and accomplishes its enzymatic action in two half-cycles (corresponding to the oxidation and reduction of O(2)(*-)). Despite many experimental and theoretical studies dealing with SODs, including quantum chemical active-site-model studies of numerous variants of the reaction mechanisms, several details of MnSOD enzymatic action are still unclear. In this study, we have modeled and compared four reaction pathways (one associative, one dissociative, and two second-sphere) in a protein environment using the QM/MM approach (combined quantum and molecular mechanics calculations) at the density functional theory level. The results were complemented by CASSCF/CASPT2/MM single-point energy calculations for the most plausible models to account properly for the multireference character of the various spin multiplets. The results indicate that the oxidation of O(2)(*-) to O(2) most likely occurs by an associative mechanism following a two-state (quartet-octet) reaction profile. The barrier height is estimated to be less than 25 kJ.mol(-1). On the other hand, the conversion of O(2)(*-) to H(2)O(2) is likely to take place by a second-sphere mechanism, that is, without direct coordination of the superoxide radical to the manganese center. The reaction pathway involves the conical intersection of two quintet states, giving rise to an activation barrier of approximately 60 kJ.mol(-1). The calculations also indicate that the associative mechanism can represent a competitive pathway in the second half-reaction with the overall activation barrier being only slightly higher than the activation barrier in the second-sphere mechanism. The activation barriers along the proposed reaction pathways are in very good agreement with the experimentally observed reaction rates of SODs (k(cat) approximately 10(4)-10(5) s(-1)).
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| 52. |
- Söderhjelm, Pär, et al.
(författare)
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Accuracy of distributed multipoles and polarizabilities: Comparison between the LoProp and MpProp models
- 2007
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Ingår i: Journal of Computational Chemistry. - : Wiley. - 1096-987X .- 0192-8651. ; 28:6, s. 1083-1090
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Tidskriftsartikel (refereegranskat)abstract
- Localized multipole moments up to the fifth moment as well as localized dipole polarizabilities are calculated with the MpProp and the newly developed LoProp methods for a total of 20 molecules, predominantly derived from amino acids. A comparison of electrostatic potentials calculated from the multipole expansion obtained by the two methods with ab initio results shows that both methods reproduce the electrostatic interaction with an elementary charge with a mean absolute error of similar to 1.5 kJ/mol at contact distance and less than 0.1 kJ/mol at distances 2 angstrom further out when terms up to the octupole moments are included. The polarizabilities are tested with homogenous electric fields and are-found to have similar accuracy. The MpProp method gives better multipole moments unless diffuse basis sets are used, whereas LoProp gives better polarizabilities. (C) 2007 Wiley Periodicals, Inc.
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| 53. |
- Söderhjelm, Pär, et al.
(författare)
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Accuracy of typical approximations in classical models of intermolecular polarization
- 2008
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Ingår i: Journal of Chemical Physics. - : AIP Publishing. - 0021-9606 .- 1089-7690. ; 128:1
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Tidskriftsartikel (refereegranskat)abstract
- One of the largest limitations of standard molecular-mechanics force fields is the neglect of intermolecular polarization. Several attempts to cure this problem have been made, but the results have not always been fully satisfactory. In this paper, we present a quantitative study of the fundamental approximations that underlie polarization models for classical force fields. The induced charge density of a large set of molecular dimers is compared to supermolecular calculations for a hierarchy of simplified models. We study the effect of the Pauli principle, the local inhomogeneity of the electric field, the intramolecular coupling of the polarization response, and the fact that the induced density is a continuous function. We show that standard point-polarizability models work rather well, despite their lack of all these effects, because (1) there is a systematic error cancellation between the neglect of effects of the Pauli principle and the locally inhomogeneous electric field, and (2) the lack of intramolecular coupling and the use of a dipole expansion of the induced density have only minor effects on the polarization. However, the cancellation in (1) is not perfect, and therefore polarizable force-fields could be improved if both effects are explicitly treated.
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| 54. |
- Söderhjelm, Pär, et al.
(författare)
-
Calculation of Protein-Ligand Interaction Energies by a Fragmentation Approach Combining High-Level Quantum Chemistry with Classical Many-Body Effects
- 2009
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Ingår i: The Journal of Physical Chemistry Part B. - : American Chemical Society (ACS). - 1520-5207 .- 1520-6106. ; 113:32, s. 11085-11094
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Tidskriftsartikel (refereegranskat)abstract
- We have developed a method to estimate accurate interaction energies between a full protein and a bound ligand. It is based oil the recently proposed PMISP (polarizable multipole interaction with supermolecular pairs) method (Soderhjelm, P.; Ryde, U. J. Phys. Chem. A 2009, 113. 617), which treats electrostatic interaction by multipoles up to quadrupoles, induction by anisotropic polarizabilities, and nonclassical interactions by explicit quantum mechanical (QM) calculations, using a fragmentation approach. For a whole protein, electrostatics and induction are treated the same way, but for the nonclassical interactions, a Lennard-Jones term from a standard molecular mechanics (MM) force field (e.g., Amber) is used outside a certain distance from the ligand (4-7 angstrom). This QM/MM variant of the PMISP method is carefully tested by varying this distance. Several approximations related to the classical interactions are also evaluated. It is found that one can speed up the calculation by using density functional theory to compute multipoles and polarizabilities but that a proper treatment of polarization is important. As a demonstration of the method, the interaction energies of two ligands bound to avidin are calculated at the MP2/aug-cc-pVTZ level, with an expected relative error of 1-2%.
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| 55. |
- Söderhjelm, Pär, et al.
(författare)
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Combined computational and crystallographic study of the oxidised states of [NiFe] hydrogenase
- 2006
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Ingår i: Journal of molecular structure. Theochem. - : Elsevier BV. - 0166-1280. ; 770:1-3, s. 199-219
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Tidskriftsartikel (refereegranskat)abstract
- [NiFe] hydrogenases catalyse the reaction H2 <-> 2H(+) + 2e(-). Several states of the enzyme have been observed by spectroscopic methods. Among these, the two most oxidized states, called the unready Ni-A and Ni-SU states, have been especially intriguing, because they take a much longer time to activate than the corresponding ready Ni-B and Ni-SI states. It has recently been suggested that the unready states actually contain a (hydro)peroxide bridge between the Ni and Fe ions, in contrast to the hydroxide bridge in the ready states. In this paper, we use quantum refinement (crystallographic refinement, in which the molecular mechanics [MM] calculations, normally employed to supplement the crystallographic data, are replace by more accurate quantum mechanics [QM] calculations), combined QM/MM calculations, and accurate energy estimates to study the nature of a recent oxidised crystal structure of [NiFe] hydrogenase from Desulfovibrio fructosovorans. We show that the structure contains a mixture of several states in the active site. The experimental data is best explained by structures with a hydroxide bridge but with two of the cysteine ligands (one bridging and one terminal) partly oxidised. When the terminal Cys-543 ligand is oxidised, the sulphur occupies an alternative position, observed in several crystal structures. The Glu-25 residue, that forms a hydrogen bond to this sulphur, also changes position. A peroxide ligand may exist as a minor component in the crystal and the suggested structure is supported by the calculations. We suggest that oxidised states are slow-equilibrium mixtures of structures with a peroxide bound and structures with oxidised Cys residues, and that the former can be activated by replacement of the protonated peroxide with a H-2 or CO ligand, as has been observed in electrochemical experiments. (c) 2006 Elsevier B.V. All rights reserved.
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| 56. |
- Söderhjelm, Pär, et al.
(författare)
-
Comparison of overlap-based models for approximating the exchange-repulsion energy
- 2006
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Ingår i: Journal of Chemical Physics. - : AIP Publishing. - 0021-9606 .- 1089-7690. ; 124:24
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Tidskriftsartikel (refereegranskat)abstract
- Different ways of approximating the exchange-repulsion energy with a classical potential function have been investigated by fitting various expressions to the exact exchange-repulsion energy for a large set of molecular dimers. The expressions involve either the orbital overlap or the electron-density overlap. For comparison, the parameter-free exchange-repulsion model of the effective fragment potential (EFP) is also evaluated. The results show that exchange-repulsion energy is nearly proportional to both the orbital overlap and the density overlap. For accurate results, a distance-dependent correction is needed in both cases. If few parameters are desired, orbital overlap is superior to density overlap, but the fit to density overlap can be significantly improved by introducing more parameters. The EFP performs well, except for delocalized pi systems. However, an overlap expression with a few parameters seems to be slightly more accurate and considerably easier to approximate. (c) 2006 American Institute of Physics.
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| 57. |
- Söderhjelm, Pär, et al.
(författare)
-
Conformational dependence of charges in protein simulations
- 2009
-
Ingår i: Journal of Computational Chemistry. - : Wiley. - 1096-987X .- 0192-8651. ; 30:5, s. 750-760
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Tidskriftsartikel (refereegranskat)abstract
- We have studied the conformational dependence of molecular mechanics atomic charges for proteins by calculating the charges fitted to the quantum mechanical (QM) electrostatic potential (ESP) for all atoms in complexes between avidin and seven biotin analogues for 20 snapshots from molecular dynamics simulations. We have studied how various other charge sets reproduce those charges. The QM charges, even if averaged over all snapshots or all residues, in general have a larger magnitude than standard Amber charges, indicating that the restraint toward zero in the restrained ESP method is too strong. This has a significant influence on the electrostatic conformational energies and the interaction energy between the biotin ligand and the protein, giving a difference between the QM and Amber charges of 43 and 8 kJ/mol for the negatively charged and neutral biotin analogues, respectively (3-4%). However, this energy difference is strongly reduced if the solvation energy (calculated by the Poisson-Boltzmann or Generalized Born methods) is added, viz., to 7 kJ/mol for charged and 3 kJ/mol for uncharged ligand. In fact, charges need to be recalculated with a QM method only for residues within 7 or 4 A of the ligand, if the error should be less than 4 kJ/mol. Unfortunately, the QM charges do not give significantly better MM/PBSA estimates of ligand-binding affinities than standard Amber charges. (c) 2008 Wiley Periodicals, Inc. J Comput Chem 2008.
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| 58. |
- Söderhjelm, Pär, et al.
(författare)
-
How Accurate Can a Force Field Become? A Polarizable Multipole Model Combined with Fragment-wise Quantum-Mechanical Calculations
- 2009
-
Ingår i: Journal of physical chemistry. A. - : American Chemical Society (ACS). - 1520-5215 .- 1089-5639. ; 113:3, s. 617-627
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Tidskriftsartikel (refereegranskat)abstract
- A new method to accurately estimate the interaction energy between a large molecule and a smaller ligand is presented. The method approximates the electrostatic and induction contributions classically by multipole and polarizability expansions, but uses explicit quantum-mechanical fragment calculations for the remaining (nonclassical) contributions, mainly dispersion and exchange repulsion. Thus, it represents a limit of how accurate a force field can ever become for interaction energies if pairwise additivity of the nonclassical term is assumed (e.g., all general-purpose force fields). The accuracy is tested by considering protein-ligand model systems for which the true MP2/6-31G* interaction energies can be computed. The method is shown to be more accurate than related fragmentation approaches. The remaining error (2-5 and ∼10 kJ/mol for neutral and charged ligands, respectively) can be decreased by including the polarizing effect from surrounding fragments in the quantum-mechanical calculations.
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| 59. |
- Söderhjelm, Pär, et al.
(författare)
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Protein Influence on Electronic Spectra Modeled by Multipoles and Polarizabilities
- 2009
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Ingår i: Journal of Chemical Theory and Computation. - : American Chemical Society (ACS). - 1549-9618 .- 1549-9626. ; 5:3, s. 649-658
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Tidskriftsartikel (refereegranskat)abstract
- We have developed automatic methods to calculate multipoles and anisotropic polarizabilities for all atoms and bond centers in a protein and to include such a model in the calculation of electronic properties at any level of quantum mechanical theory. This approach is applied for the calculation of the electronic spectra of retinal in rhodopsin at the CASPT2//CASSCF level (second-order multiconfigurational perturbation theory) for the wild-type protein, as well as two mutants and isorhodopsin in QM/MM structures based on two crystal structures. We also perform a detailed investigation of the importance and distance dependence of the multipoles and the polarizabilities for both the absolute and the relative absorption energies. It is shown that the model of the surrounding protein strongly influences the spectrum and that different models give widely different results. For example, the Amber 1994 and 2003 force fields give excitation energies that differ by up to 16 kJ/mol. For accurate excitation energies, multipoles up to quadrupoles and anisotropic polarizabilities are needed. However, interactions with residues more than 10 A from the chromophore can be treated with a standard polarizable force field without any dipoles or quadrupoles.
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| 60. |
- Wang, Yaxue, et al.
(författare)
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QM/MM study of the insertion of metal ion into protoporphyrin IX by ferrochelatase
- 2009
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Ingår i: Journal of Inorganic Biochemistry. - : Elsevier BV. - 1873-3344 .- 0162-0134. ; 103:12, s. 1680-1686
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Tidskriftsartikel (refereegranskat)abstract
- Ferrochelatase catalyzes the metallation of protoporphyrin IX in the terminal step of heme biosynthesis. Mutations in the ferrochelatase gene can lead to the disease erythropoietic porphyria. The catalyzing mechanism of ferrochelatase is still not fully understood. In this paper, we have studied the insertion of Fe2+ into the protoporphyrin IX ring by Bacillus subtilis ferrochelatase using combined quantum mechanical and molecular mechanics (QM/MM) calculations. Geometries were optimized at the BP86/6-31G* level and energies were calculated at the B3LYP/TZVP level. The overall process involves the step-wise displacement of Glu-264, His-183, and a water molecule from Fe2+, and the removal of two protons from the porphyrin ring. The rate-determining step is the cleavage of the bond between the oxygen atom of Glu-264 and Fe2+, concomitant with the formation of the first Fe-N bond. It has an energy barrier of 57 kJ mol(-1). The porphyrin ring is only slightly distorted in the enzyme active site. The residue Tyr-13 plays a key role for the catalytic process extracting two protons from protoporphyrin IX. (C) 2009 Elsevier Inc. All rights reserved.
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