| 1. |
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| 2. |
- Himo, Fahmi, et al.
(författare)
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Relative acidities of ortho-substituted phenols, as models for modified tyrosines in proteins
- 2002
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Ingår i: Journal of Physical Chemistry A. - : American Chemical Society (ACS). - 1089-5639 .- 1520-5215. ; 106:37, s. 8757-8761
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Tidskriftsartikel (refereegranskat)abstract
- The effects of a variety of ortho-substituents (CH3, OH, OCH3, SH, SCH3, NH2, NO2, F, Cl, CN, and imidazole) on the acidity of phenol are investigated using hybrid density functional theory. Substitutions are made at the ortho-position to model modified tyrosine residues found in enzymes. Although the experimental trends are reproduced, the calculations tend to exaggerate the substituent effects. It is shown that the cysteine cross-link to tyrosine, present in the radical enzyme galactose oxidase, has a small effect on the pK(a) of the residue. The histidine cross-link present in cytochrome c oxidase, on the other hand, will contribute more to. lower the pKa. Comparing the substituent effects on the O-H bond strengths and the acidities, no simple correlation is found between the two.
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| 3. |
- Himo, Fahmi, et al.
(författare)
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Substituent effects on OH bond strength and hyperfine properties of phenol, as model for modified tyrosyl radicals in proteins
- 2000
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Ingår i: International Journal of Quantum Chemistry. - 0020-7608 .- 1097-461X. ; 76:6, s. 714-723
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Tidskriftsartikel (refereegranskat)abstract
- Density functional theory is used to investigate the effects of a variety of substituents (CH3, OH, OCH3, SH, SCH3, NH2, NMe2, NO2, F, Cl, CN, and imidazole) on the phenol O-H bond dissociation energy (BDE) and phenoxyl radical hyperfine properties. Substitutions are made at the ortho position to model modified tyrosine residues found in enzymes. The calculations show that besides the electronic effects of the substituents, intramolecular hydrogen bonds between OH and the substituents will contribute considerably to stabilize the parent species. Substituent effects on anisole O-Me bond strengths can thus not correctly describe the effects on ortho-substituted phenol O-H bond strengths, as previously proposed. This fact is supported by a series of calculations on o-substituted anisoles. The odd-alternant spin pattern of the phenoxyl radical is conserved for most of the substitutions. In particular, it is predicted that the cysteine crosslink to tyrosine, present in the radical enzyme galactose oxidase, and the histidine crosslink, present in cytochrome-c oxidase, will only have minor effects on the BDE and the radical hyperfine coupling constants and spin distribution of the tyrosyl radical.
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| 4. |
- Lundberg, Marcus, 1974-, et al.
(författare)
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Modeling water exchange on monomeric and dimeric Mn centers
- 2003
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Ingår i: Theoretical Chemistry accounts. - : Springer Science and Business Media LLC. - 1432-881X .- 1432-2234. ; 110:3, s. 130-143
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Tidskriftsartikel (refereegranskat)abstract
- Water exchange on Mn centers in proteins has been modeled with density functional theory using the B3LYP functional. The reaction barrier for dissociative water exchange on [Mn-IV(H2O)(2)(OH)(4)] is only 9.6 kcal mol(-1), corresponding to a rate of 6 x 10(5) s(-1). It has also been investigated how modifications of the model complex change the exchange rate. Three cases of water exchange on Mn dimers have been modeled. The reaction barrier for dissociative exchange of a terminal water ligand on [(H2O)(2)(OH)(2)Mn-IV(mu-O)(2)Mn-IV(H2O)(2) (OH)(2)] is 8.6 kcal mol(-1), while the bridging oxo group exchange with a ring-opening mechanism has a barrier of 19.2 kcal mol(-1). These results are intended for interpretations of measurements of water exchange for the oxygen evolving complex of photosystem II. Finally, a tautomerization mechanism for exchange of a terminal oxyl radical has been modeled for the synthetic 02 catalyst [(terpy)(H2O)Mn-IV(mu-O)(2)Mn-IV(O.)(terpy)](3+) (terpy=2,2':6,2"-terpyridine). The calculated reaction barrier is 14.7 kcal mol(-1).
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| 5. |
- Cho, K. B., et al.
(författare)
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The substrate reaction mechanism of class III anaerobic ribonucleotide reductase
- 2001
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Ingår i: Journal of Physical Chemistry B. - : American Chemical Society (ACS). - 1089-5647 .- 1520-6106 .- 1520-5207. ; 105:27, s. 6445-6452
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Tidskriftsartikel (refereegranskat)abstract
- The substrate mechanism of class III anaerobic ribonucleotide reductase has been studied using quantum chemical methods. The study is based on the previously suggested mechanism for the aerobic class I enzyme, together with the recently determined X-ray structure of the anaerobic enzyme. The initial steps are similar in the mechanisms of these enzymes, but for the suggested rate-limiting steps there are key differences. In the class I enzyme, the 3 ' -keto group of the substrate is protonated in a step involving formation of a sulfur-sulfur bond between two cysteines, One of these cysteines is not present in the anaerobic enzyme. Instead, carbon dioxide is formed in this step from formate, which is present as a cofactor. In line with previous suggestions from experimental observations, the formate first forms a formyl radical. The next step, where the formyl radical protonates the 3 ' -keto group of the substrate, is suggested to be rate limiting with a calculated total barrier of 19.9 kcal/mol, in reasonable agreement with the experimental rate-limiting barrier of 17 kcal/mol. Zero-point and entropy effects are found to be quite significant in lowering the barrier. The mechanism for the entire cycle is discussed in relation to known experimental facts.
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| 6. |
- Himo, Fahmi, et al.
(författare)
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Catalytic mechanism of galactose oxidase : A theoretical study
- 2000
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 122:33, s. 8031-8036
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Tidskriftsartikel (refereegranskat)abstract
- Density functional methods, alone and together with molecular mechanics, are used to study the catalytic mechanism of galactose oxidase. This enzyme catalyzes the conversion of primary alcohols to the corresponding aldehydes, coupled with reduction of dioxygen to hydrogen peroxide. It is shown that the proposed mechanism for this enzyme is energetically feasible. In particular the barrier for the postulated rate-limiting hydrogen atom, transfer between the substrate and the tyrosyl radical, located at equatorial Tyr272, is very plausible. We propose that the radical site, prior to the initial proton transfer step, is located at the axial tyrosine (Tyr495). The radical is transferred to the equatorial tyrosine (Tyr272) simultaneously with the proton transfer. It is, furthermore, argued that the electron transfer from the ketyl radical intermediate to Cu(II) cannot be very exothermic, because this would render the oxygen reduction steps rate-limiting. Finally, the cysteine cross-link on the active site tyrosine is shown to have very minor effects on the energetics of the reaction.
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| 7. |
- Himo, Fahmi, et al.
(författare)
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Catalytic mechanism of glyoxalase I : A theoretical study
- 2001
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 123:42, s. 10280-10289
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Tidskriftsartikel (refereegranskat)abstract
- Hybrid density functional theory is used to study the catalytic mechanism of human glyoxalase I (GlxI). This zinc enzyme catalyzes the conversion of the hemithioacetal of toxic methylglyoxal and glutathione to nontoxic (S)-D-lactoylglutathione. GlxI can process both diastereomeric forms of the substrate, yielding the same form of the product. As a starting point for the calculations, we use a recent crystal structure of the enzyme in complex with a transition-state analogue, where it was found that the inhibitor is bound directly to the zinc by its hydroxycarbamoyl functions. It is shown that the Zn ligand Glu172 can abstract the substrate Cl proton from the S enantiomer of the substrate, without being displaced from the Zn ion. The calculated activation barrier is in excellent agreement with experimental rates. Analogously, the Zn ligand Glu99 can abstract the proton from the R form of the substrate. To account for the stereochemical findings, it is argued that the S and R reactions cannot be fully symmetric. A detailed mechanistic scheme is proposed.
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| 8. |
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| 9. |
- Himo, Fahmi, et al.
(författare)
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Very stable ribonucleotide substrate radical relevant for class I ribonucleotide reductase
- 2000
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Ingår i: Journal of Physical Chemistry B. - : American Chemical Society (ACS). - 1089-5647 .- 1520-6106 .- 1520-5207. ; 104:31, s. 7502-7509
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Tidskriftsartikel (refereegranskat)abstract
- In recent experimental studies on the E441Q mutant of ribonucleotide reductase, a new substrate radical was discovered on the minute time scale. This radical is kinetically coupled to a cysteine-based radical appearing on the 10 s time scale. In the present study, density functional calculations have been performed to investigate the nature of these radicals. The most interesting result is that a very stable substrate radical was found, which lies outside the normal substrate pathway. This radical is so stable that its creation has to be avoided by the enzyme, or the substrate reactions would be slowed by several orders of magnitude. It is suggested that the enzyme accomplishes this task by considerably straining the mobility of the Cys225 residue. A previously suggested reaction mechanism is modified to take these recent findings into account. The modification does not significantly change the energetics of the model reactions.
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| 10. |
- James, Stefan K., et al.
(författare)
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Activation of the inflammation, coagulation, and fibrinolysis systems, without influence of abciximab infusion in patients with non-ST–elevation acute coronary syndromes treated with dalteparin : a GUSTO IV substudy
- 2004
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Ingår i: American Heart Journal. - : Elsevier BV. - 0002-8703 .- 1097-6744. ; 147:2, s. 267-274
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundIn acute coronary syndromes, the inflammation and the coagulation systems are activated, implying an impaired outcome. In addition to platelet inhibition, recent evidence suggests that the glycoprotein IIb/IIIa receptor inhibitor abciximab attenuates inflammation and coagulation activity.MethodsThe Swedish Global Utilization of Strategies To open Occluded arteries-IV (GUSTO-IV) substudy included 404 patients with non-ST–elevation acute coronary syndromes. In addition to aspirin and dalteparin, all patients were randomized to receive abciximab infusion for 24 hours or 48 hours or corresponding placebo without early coronary revascularization. Plasma samples were obtained at baseline and 24, 48, and 72 hours.ResultsThe median levels of the coagulation markers thrombin/antithrombin complex and soluble fibrin increased significantly from 3.1 to 3.7 ug/L (baseline to peak; P <.001) and from 20 to 23 nmol/L (P <.001), respectively. The fibrinolysis marker, tissue plasminogen-activator, also increased its median levels, from 11.7 to 17.5 ug/L (P <.001), whereas the median level of plasminogen-activator-inhibitor was unchanged. The inflammatory markers interleukin-6, C-reactive protein, and fibrinogen also increased their median levels (5.4–7.8 ng/L, P <.001; 4.4–8.7 mg/L, P <.001; 3.3–3.9 g/L, P <.001). However, there were no differences in median levels or in changes of median levels of any marker at any point between the placebo group and any of the abciximab groups.ConclusionsIn non-ST–elevation acute coronary syndrome, there was a simultaneous activation of the inflammation, coagulation, and fibrinolysis systems, despite aspirin and dalteparin treatment. Prolonged treatment with abciximab had no influence of the activation of these systems.Unstable coronary artery disease (CAD) intricately involves inflammatory mediators in the development of an atherosclerotic plaque and in thrombus formation by platelet aggregation.1 Acute phase elevation of inflammatory markers such as C-reactive protein (CRP), interleukin-6 (IL-6), and fibrinogen are important predictors of the short- and long-term prognosis in unstable CAD.2, 3 and 4 Activation of the coagulation and fibrinolysis systems, as demonstrated with elevated markers of thrombin generation, thrombin activity, and fibrin turnover, also have been found in the acute phase of unstable CAD and are associated with an adverse outcome.5, 6 and 7 Glycoprotein IIb/IIIa (GP IIb/IIIa) inhibitors potently inhibit platelet aggregation and reduce the incidence of ischemic events in patients undergoing percutaneuos coronary interventions8, 9 and 10 and in patients with unstable CAD.11 The GP IIb/IIIa inhibitor abciximab, in addition to its antithrombotic effect, also suppresses the rise in levels of inflammatory markers after percutaneous coronary interventions.12 This anti-inflammatory effect might be related to abciximab's cross-reaction with other integrin receptors.13 Furthermore, by inhibiting platelet aggregation, abciximab might also attenuate the coagulation and fibrinolysis activation as shown in vitro and in vivo.14 and 15The Global Utilization of Strategies To Open occluded arteries in acute coronary syndromes (GUSTO IV-ACS) trial unexpectedly failed to show any benefit of abciximab treatment in a high risk ACS population not undergoing early coronary revascularization.16 In the GUSTO IV-ACS low-molecular weight heparin substudy,17 dalteparin was used as the anticoagulant. Dalteparin, which is an inhibitor of the coagulation cascade, mainly by inhibition of factor Xa and less of factor IIa, has previously been shown to reduce the generation and activity of thrombin in unstable coronary disease.18 There is evidence that a combination of abciximab and a low-molecular-weight heparin have additive effects on the lag-time to platelet aggregation,19 and there are several theoretical advantages with the combination treatment. There was still no significant reduction in clinical events with abciximab in combination with dalteparin.17 The aim of this Swedish substudy of GUSTO IV-ACS was to evaluate the influence of abciximab infusion on markers on inflammation, coagulation, and fibrinolysis in patients with unstable CAD treated with aspirin and subcutaneous dalteparin.
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| 11. |
- Karlsson, P G, et al.
(författare)
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Interfacial properties of the nanostructured dye-sensitized solid heterojunction TiO2/RuL2(NCS)(2)/CuI
- 2004
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Ingår i: Journal of Chemical Physics. - : AIP Publishing. - 0021-9606 .- 1089-7690. ; 120:23, s. 11224-11232
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Tidskriftsartikel (refereegranskat)abstract
- The interfaces of the nanostructured dye-sensitized solid heterojunction TiO2/Ru-dye/CuI have been studied using photoelectron spectroscopy of core and valence levels, x-ray absorption spectroscopy and atomic force microscopy. A nanostructured anatase TiO2 film sensitized with RuL2(NCS)(2) [cis-bis(4,4'-dicarboxy-2,2'-bipyridine)-bis(isothio-cyanato)-ruthenium(II)] was prepared in a controlled way using a novel combined in-situ and ex-situ (Ar atmosphere) method. Onto this film CuI was deposited in-situ. The formation of the dye-CuI interface and the changes brought upon the dye-TiO2 interface could be monitored in a stepwise fashion. A direct interaction between the dye NCS groups and the CuI is evident in the core level photoelectron spectra. Concerning the energy matching of the valence electronic levels, the photoelectron spectra indicate that the dye HOMO overlaps in energy with the Cu 3d-I 5p hydrid states. The CuI grow in the form of particles, which at the initial stages displace the dye molecules causing dye-TiO2 bond breaking. Consequently, the very efficient charge injection channel provided by the dye-TiO2 carboxylic bonding is directly affected for a substantial part of the dye molecules. This may be of importance for the functional properties of such a heterojunction. (C) 2004 American Institute of Physics.
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| 12. |
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| 13. |
- Lundberg, Marcus, 1974-, et al.
(författare)
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Theoretical investigations of structure and mechanism of the oxygen-evolving complex in PSII
- 2004
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Ingår i: Physical Chemistry, Chemical Physics - PCCP. - : Royal Society of Chemistry (RSC). - 1463-9076 .- 1463-9084. ; 6:20, s. 4772-4780
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Tidskriftsartikel (refereegranskat)abstract
- Hybrid density functional theory has been used to study a proposed Mn3Ca-Mn cubane-like structure for the oxygen-evolving complex in photosystem II. A refined analysis of the structure is made regarding the position of the heavy atoms, the oxidation states of the manganese centers and the protonation states of the ligands. After finding the most stable S-2 structure, S-0 --> S-1 and S-1 --> S-2 transitions are proposed. Further, proposals for the higher S state transitions, S-2 --> S-3 and S-3 --> S-4 have been investigated, using the O-H bond dissociation energy as a probe. With an intact cubane-like structure, oxidation to a high valent Mn-oxo species has so far not been found to be energetically feasible. Instead, tentative proposals of the S-2 --> S-3 transition involving structural rearrangements are made.
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| 14. |
- Prabhakar, R., et al.
(författare)
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Activation of triplet dioxygen by glucose oxidase : Spin-orbit coupling in the superoxide ion
- 2002
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Ingår i: Journal of Physical Chemistry B. - : American Chemical Society (ACS). - 1520-6106 .- 1520-5207. ; 106:14, s. 3742-3750
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Tidskriftsartikel (refereegranskat)abstract
- Hybrid density functional calculations have been performed for the reductive activation of dioxygen by glucose oxidase, for which recent experiments have shown substantial kinetic O-18 isotope effects but no deuterium isotope effect, The present analysis of the mechanism suggests that this surprising isotope effect is best explained if the rate-determining step is the triplet --> singlet interconversion that follows after the electron transfer and the superoxide ion production. The oxygen isotope effect is rationalized by an analysis of the spin-orbit coupling in the radical pair M.+..O-2(.-), where M is the FADH(2) cofactor. For the electron transfer between the M and O-2, the presence of the protonated His516 plays a crucial role by strongly increasing the electron affinity Of O-2, which makes the electron transfer exothermic and allows it to occur without any barrier. The chemical step where hydrogen peroxide is formed has a computed free-energy barrier of only 6.6 kcal/mol.
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| 15. |
- Prabhakar, R., et al.
(författare)
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Spin transition during H2O2 formation in the oxidative half-reaction of copper amine oxidases
- 2004
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Ingår i: Journal of Physical Chemistry B. - : American Chemical Society (ACS). - 1520-6106 .- 1520-5207. ; 108:36, s. 13882-13892
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Tidskriftsartikel (refereegranskat)abstract
- Dioxygen reduction in the oxidative half-reaction of copper amine oxidases (CAOs) has been studied quantum chemically using the hybrid density functional theory (B3LYP). The reductive activation of dioxygen is a spin-forbidden process for which substantial kinetic O-18 (but no deuterium) isotope effects have been found experimentally. The proposed mechanism was divided into three steps, and the last step was studied for two different potential energy surfaces: the quartet and the doublet surfaces. It is suggested that dioxygen reduction occurs through a spin transition that is induced by the exchange interaction between the impaired spins of the Cu(II) ion and the O-2(-) anion. The step involving this spin transition is suggested to be rate-limiting, which gives a rationalization for the puzzling experimental results when copper is substituted for other metals. The spin transition is triggered by the calculated vibronic perturbation of 5.4 (kcal/mol) Angstrom(-1), which leads to a very fast rate of 8 x 10(10) s(-1) for the spin transition. However, since the spin transition occurs at a calculated energy that is 18-20 kcal/mol higher than that of the reactant, this step could still be rate-limiting. The difference in the O-O bond distance between the resting state (free dioxygen) and the point of the spin transition provides an explanation for the oxygen isotope effect.
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