| 1. |
- Kawatsu, Tsutomu, et al.
(författare)
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Protein Free Energy Corrections in ONIOM QM:MM Modeling : A Case Study for Isopenicillin N Synthase (IPNS)
- 2011
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Ingår i: Journal of Chemical Theory and Computation. - : American Chemical Society. - 1549-9618 .- 1549-9626. ; 7:2, s. 390-401
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Tidskriftsartikel (refereegranskat)abstract
- The protein environment can have significant effects on the enzyme catalysis even though the reaction occurs locally at the reaction center. In this paper, we describe an efficient scheme that includes a classical molecular dynamics (MD) free-energy perturbation (FEP) correction to the reaction energy diagram, as a complement to the protein effect obtained from static ONIOM (QM:MM) calculations. The method is applied to eight different reaction steps, from the O2-bound reactant to formation of a high-valent ferryl-oxo intermediate, in the nonheme iron enzyme isopenicillin N synthase (IPNS), for which the QM:MM energy diagram has previously been computed [ Lundberg, M. et al. J. Chem. Theory Comput. 2009, 5, 220 ‚àí 234 ]. This large span of the reaction coordinate is covered by dividing each reaction step into microsteps using a virtual reaction coordinate, thus only requiring ONIOM information about the stationary points themselves. Protein effects are important for C‚àíH bond activation and heterolytic O‚àíO bond cleavage because both these two steps involve charge transfer, and compared to a static QM:MM energies, the dynamics of the protein environment changes the barrier for O‚àíO bond cleavage by several kcal/mol. The origin of the dynamical contribution is analyzed in two terms, the geometrical effect caused by the change in average protein geometry (compared to the optimized geometry) in the room temperature MD simulation with the solvent, and the statistical (entropic) effect resulting from fluctuations in the interactions between the active site and the protein environment. These two effects give significant contributions in different steps of the reaction.
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| 2. |
- Lundberg, Marcus, 1974-, et al.
(författare)
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Determining Transition States in Bioinorganic Reactions
- 2009
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Ingår i: Computational Inorganic and Bioinorganic Chemistry. - Hoboken : John Wiley & Sons, Ltd. - 9780470699973 ; , s. 17-31
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Bokkapitel (övrigt vetenskapligt/konstnärligt)
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| 3. |
- Lundberg, Marcus, 1974-, et al.
(författare)
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Protein environment facilitates O-2 binding in non-heme iron enzyme : An insight from ONIOM calculations on isopenicillin N synthase (IPNS)
- 2007
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Ingår i: Journal of Physical Chemistry B. - : American Chemical Society (ACS). - 1520-6106 .- 1520-5207. ; 111:31, s. 9380-9389
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Tidskriftsartikel (refereegranskat)abstract
- Binding of dioxygen to a non-heme enzyme has been modeled using the ONIOM combined quantum mechanical/molecular mechanical (QM/MM) method. For the present system, isopenicillin N synthase (IPNS), binding of dioxygen is stabilized by 8-10 kcal/mol for a QM:MM (B3LYP:Amber) protein model compared to a quantum mechanical model of the active site only. In the protein system, the free energy change of O-2 binding is close to zero. Two major factors consistently stabilize O-2 binding. The first effect, evaluated at the QM level, originates from a change in coordination geometry of the iron center. The active-site model artificially favors the deoxy state (O-2 not bound) because it allows too-large rearrangements of the five-coordinate iron site. This error is corrected when the protein is included. The corresponding effect on binding energies is 3-6 kcal/mol, depending on the coordination mode of O-2 (side-on or end-on). The second major factor that stabilizes O-2 binding is van der Waals interactions between dioxygen and the surrounding enzyme. These interactions, 3-4 kcal/mol at the MM level, are neglected in models that include only the active site. Polarization of the active site by surrounding amino acids does not have a significant effect on the binding energy in the present system.
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| 4. |
- Lundberg, Marcus, 1974-, et al.
(författare)
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The mechanism for isopenicillin N synthase from density-functional modeling highlights the similarities with other enzymes in the 2-his-1-carboxylate family
- 2008
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Ingår i: Biochemistry. - : American Chemical Society (ACS). - 0006-2960 .- 1520-4995. ; 47:3, s. 1031-1042
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Tidskriftsartikel (refereegranskat)abstract
- Isopenicillin N synthase (IPNS) catalyzes a key step in the biosynthesis of the important P-lactam antibiotics penicillins and cephalosporins. Density-functional calculations with the B3LYP functional are used to propose a detailed mechanism for this reaction. The results support the general scheme outlined from experimental observations, with formation of a four-membered beta-lactam ring followed by formation of a five-membered thiazolidine ring. However, an alternative mechanism for the heterolytic O-O bond cleavage and beta-lactam ring formation steps is proposed. The former part involves protonation of the distal oxygen by an iron-bound water ligand. This mechanism highlights the strong similarities that exist between IPNS and other enzymes of the 2-histidine-1-carboxylate family, especially pterin-dependent amino acid hydroxylases and alpha-keto acid-dependent dioxygenases. Both activation of the cysteine beta-C-H bond by an iron-bound superoxo radical and activation of the valine beta-C-H bond by a ferryl-oxo species show reaction barriers close to the experimentally measured one. These results are in agreement with kinetic isotope experiments that suggest both C-H bond activation steps to be partially rate limiting. The ring formation sequence is determined by the relative strengths of the two C-H bonds. Only the ferryl-oxo intermediate is capable of activating the stronger valine beta-C-H bond.
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| 5. |
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| 6. |
- Stickley, Andrew, et al.
(författare)
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Assessment of Autistic Traits in Children Aged 2 to 4½ Years With the Preschool Version of the Social Responsiveness Scale (SRS-P) : Findings from Japan
- 2017
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Ingår i: Autism Research. - : John Wiley & Sons. - 1939-3792 .- 1939-3806. ; 10:5, s. 852-865
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Tidskriftsartikel (refereegranskat)abstract
- The recent development and use of autism measures for the general population has led to a growing body of evidence which suggests that autistic traits are distributed along a continuum. However, as most existing autism measures were designed for use in children older than age 4, to date, little is known about the autistic continuum in children younger than age 4. As autistic symptoms are evident in the first few years, to address this research gap, the current study tested the preschool version of the Social Responsiveness Scale (SRS-P) in children aged 2 to 4½ years in clinical (N = 74, average age 40 months, 26-51 months) and community settings (N = 357, average age 39 months, 25-50 months) in Japan. Using information obtained from different raters (mothers, other caregivers, and teachers) it was found that the scale demonstrated a good degree of internal consistency, inter-rater reliability and test-retest reliability, and a satisfactory degree of convergent validity for the clinical sample when compared with scores from diagnostic "gold standard" autism measures. Receiver operating characteristic analyses and the group comparisons also showed that the SRS-P total score discriminated well between children with autism spectrum disorder (ASD) and those without ASD. Importantly, this scale could identify autistic symptoms or traits distributed continually across the child population at this age irrespective of the presence of an ASD diagnosis. These findings suggest that the SRS-P might be a sensitive instrument for case identification including subthreshold ASD, as well as a potentially useful research tool for exploring ASD endophenotypes. Autism Res 2016.
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| 7. |
- Zheng, Guishan, et al.
(författare)
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Implementation and Benchmark Tests of the DFTB Method and Its Application in the ONIOM Method
- 2009
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Ingår i: International Journal of Quantum Chemistry. - : Wiley. - 0020-7608 .- 1097-461X. ; 109:9, s. 1841-1854
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Tidskriftsartikel (refereegranskat)abstract
- We present the theoretical and implementation details of the DFTB method with analytical gradients into the Gaussian package. SCF optimization performance with DIIS method is compared with modified Broyden method and Anderson methods, from which DIIS method is to be preferred. The number of geometry optimization steps can be significantly decreased with the Berny algorithm compared to the conjugated gradient method. From the comparison of geometry parameters as well as trends in the change of HOMO and LUMO energies, the results show clearly that DFTB can reproduce values obtained at the B3LYP/6-31G(d) level well. We also investigated the DFTB method as the low level quantum mechanical (QM) method in an ONIOM (QM:QM') description for all amino acid model system and found DFTB promising as a method to describe polarization and charge-transfer effects in large systems.
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| 8. |
- Zheng, Guishan, et al.
(författare)
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Parameter calibration of transition-metal elements for the spin-polarized self-consistent-charge density-functional tight-binding (DFTB) method : Sc, Ti, Fe, Co, and Ni
- 2007
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Ingår i: Journal of Chemical Theory and Computation. - : American Chemical Society (ACS). - 1549-9618 .- 1549-9626. ; 3:4, s. 1349-1367
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Tidskriftsartikel (refereegranskat)abstract
- Recently developed parameters for five first-row transition-metal elements (M = Sc, Ti, Fe, Co, and Ni) in combination with H, C, N, and O as well as the same metal (M-M) for the spin-polarized self-consistent-charge density-functional tight-binding (DFTB) method have been calibrated. To test their performance a couple sets of compounds have been selected to represent a variety of interactions and bonding schemes that occur frequently in transition-metal containing systems. The results show that the DFTB method with the present parameters in most cases reproduces structural properties very well, but the bond energies and the relative energies of different spin states only qualitatively compared to the B3LYP/SDD+6-31G(d) density functional (DFT) results. An application to the ONIOM(DFT:DFTB) indicates that DFTB works well as the low level method for the ONIOM calculation.
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