| 1. |
- Gerlach, L O, et al.
(författare)
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Metal ion enhanced binding of amd3100 to asp-262 in the cxcr4 receptor.
- 2003
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Ingår i: Biochemistry. - : American Chemical Society (ACS). - 0006-2960 .- 1520-4995. ; 42:3, s. 710-717
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Tidskriftsartikel (refereegranskat)abstract
- The affinity of AMD3100, a symmetrical nonpeptide antagonist composed of two 1,4,8,11-tetraazacyclotetradecane (cyclam) rings connected through a 1,4-dimethylene(phenylene) linker to the CXCR4 chemokine receptor was increased 7, 36, and 50-fold, respectively, by incorporation of the following: Cu2+, Zn2+, or Ni2+ into the cyclam rings of the compound. The rank order of the transition metal ions correlated with the calculated binding energy between free acetate and the metal ions coordinated in a cyclam ring. Construction of AMD3100 substituted with only a single Cu2+ or Ni2+ ion demonstrated that the increase in binding affinity of the metal ion substituted bicyclam is achieved through an enhanced interaction of just one of the ring systems. Mutational analysis of potential metal ion binding residues in the main ligand binding crevice of the CXCR4 receptor showed that although binding of the bicyclam is dependent on both Asp171 and Asp262, the enhancing effect of the metal ion was selectively eliminated by substitution of Asp262 located at the extracellular end of TM-VI. It is concluded that the increased binding affinity of the metal ion substituted AMD3100 is obtained through enhanced interaction of one of the cyclam ring systems with the carboxylate group of Asp262. It is suggested that this occurs through a strong concomitant interaction of one of the oxygen's directly with the metal ion and the other oxygen to one of the nitrogens of the cyclam ring through a hydrogen bond.
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| 2. |
- Heimdal, Jimmy, et al.
(författare)
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The role of axial ligands for the structure and function of chlorophylls
- 2007
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Ingår i: Journal of Biological Inorganic Chemistry. - : Springer Science and Business Media LLC. - 1432-1327 .- 0949-8257. ; 12:1, s. 49-61
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Tidskriftsartikel (refereegranskat)abstract
- We have studied the effect of axial ligation of chlorophyll and bacteriochlorophyll using density functional calculations. Eleven different axial ligands have been considered, including models of histidine, aspartate/glutamate, asparagine/glutamine, serine, tyrosine, methionine, water, the protein backbone, and phosphate. The native chlorophylls, as well as their cation and anion radical states and models of the reaction centres P680 and P700, have been studied and we have compared the geometries, binding energies, reduction potentials, and absorption spectra. Our results clearly show that the chlorophylls strongly prefer to be five-coordinate, in accordance with available crystal structures. The axial ligands decrease the reduction potentials, so they cannot explain the high potential of P680. They also redshift the Q band, but not enough to explain the occurrence of red chlorophylls. However, there is some relation between the axial ligands and their location in the various photosynthetic proteins. In particular, the intrinsic reduction potential of the second molecule in the electron transfer path is always lower than that of the third one, a feature that may prevent back-transfer of the electron.
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| 3. |
- Jensen, Kasper, et al.
(författare)
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Cobalamins uncovered by modern electronic structure calculations
- 2009
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Ingår i: Coordination Chemistry Reviews. - : Elsevier BV. - 0010-8545. ; 253:5-6, s. 769-778
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Forskningsöversikt (refereegranskat)abstract
- This review describes how computational methods have contributed to the held of cobalamin chemistry since the start of the new millennium. Cobalamins are cobalt-dependent cofactors that are used for alkyl transfer and radical initiation by several classes of enzymes. Since the entry of modern electronic-structure calculations, in particular density functional methods, the understanding of the molecular mechanism of cobalamins has changed dramatically, going from a dominating view of trans-steric strain effects to a much more complex view involving an arsenal of catalytic strategies. Among these are cis-steric distortions, electrostatic stabilization of radical products, the realization that nucleotide units can serve as polar handles, and the careful design of the active sites, with polar residues in the radical enzymes and non-polar residues in the transferases. Together, these strategies explain the enigmatic Co-C bond cleavage necessary for catalysis by these enzymes. (C) 2008 Elsevier B.V. All rights reserved.
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| 4. |
- Jensen, Kasper, et al.
(författare)
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Comparison of chemical properties of iron, cobalt, and nickel porphyrins, corrins, and hydrocorphins
- 2005
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Ingår i: Journal of Porphyrins and Phthalocyanines. - 1099-1409. ; 9:8, s. 581-606
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Tidskriftsartikel (refereegranskat)abstract
- Density functional calculations have been used to compare the geometric, electronic, and functional properties of the three important tetrapyrrole systems in biology, heme, coenzyme B12, and coenzyme F430, formed from iron porphyrin (Por), cobalt corrin (Cor), and nickel hydrocorphin (Hcor). The results show that the flexibility of the ring systems follows the trend Hcor > Cor > Por and that the size of the central cavity follows the trend Cor < Por < Hcor. Therefore, low-spin CoI, CoII, and CoIII fit well into the Cor ring, whereas Por seems to be more ideal for the higher spin states of iron, and the cavity in Hcor is tailored for the larger Ni ion, especially in the high-spin NiII state. This is confirmed by the thermodynamic stabilities of the various combinations of metals and ring systems. Reduction potentials indicate that the +I and +III states are less stable for Ni than for the other metal ions. Moreover, Ni–C bonds are appreciably less stable than Co-C bonds. However, it is still possible that a Ni–CH3 bond is formed in F430 by a heterolytic methyl transfer reaction, provided that the donor is appropriate, e.g. if coenzyme M is protonated. This can be facilitated by the adjacent SO3‑ group in this coenzyme and by the axial glutamine ligand, which stabilizes the NiIII state. Our results also show that a NiIII–CH3 complex is readily hydrolysed to form a methane molecule and that the NiIII hydrolysis product can oxidize coenzyme B and M to a heterodisulphide in the reaction mechanism of methyl coenzyme M reductase.
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| 5. |
- Jensen, Kasper, et al.
(författare)
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Comparison of the chemical properties of iron and cobalt porphyrins and corrins.
- 2003
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Ingår i: ChemBioChem. - : Wiley. - 1439-4227. ; 4:5, s. 413-424
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Tidskriftsartikel (refereegranskat)abstract
- Density functional calculations have been used to compare various geometric, electronic and functional properties of iron and cobalt porphyrin (Por) and corrin (Cor) species. The investigation is focussed on octahedral MII/III complexes (where M is the metal) with two axial imidazole ligands (as a model of b and c type cytochromes) or with one imidazole and one methyl ligand (as a model of methylcobalamin). However, we have also studied some five-coordinate MII complexes with an imidazole ligand and four-coordinate MI/II complexes without any axial ligands as models of other intermediates in the reaction cycle of coenzyme B12. The central cavity of the corrin ring is smaller than that of porphine. We show that the cavity of corrin is close to ideal for low-spin CoIII, CoII, and CoI with the axial ligands encountered in biology, whereas the cavity in porphine is better suited for intermediate-spin states. Therefore, the low-spin state of Co is strongly favoured in complexes with corrins, whereas there is a small energy difference between the various spin states in iron porphyrin species. There are no clear differences for the reduction potentials of the octahedral complexes, but [CoICor] is more easily formed (by at least 40 kJ mole-1) than [FeIPor]. Cobalt and corrin form a strong CoC bond that is more stable against hydrolysis than iron and porphine. Finally, FeII/III gives a much lower reorganisation energy than CoII/III; this is owing to the occupied dz2 orbital in CoII. Altogether, these results give some clues about how nature has chosen the tetrapyrrole rings and their central metal ion.
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| 6. |
- Jensen, Kasper, et al.
(författare)
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Conversion of homocysteine to methionine by methionine synthase: a density functional study.
- 2003
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 1520-5126 .- 0002-7863. ; 125:46, s. 13970-13971
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Tidskriftsartikel (refereegranskat)abstract
- This communication reports a theoretical study of the conversion of homocysteine to methionine by methionine synthase. The reaction pathway is based on density functional calculations with large basis sets, including thermodynamic, relativistic, and solvent effects. We find that the suggested SN2 mechanism explains well the experimentally observed reaction rate. The results show that the reaction is highly polar, as reflected in the change of charge density along the reaction coordinate. It is enhanced in the protein by two effects: deprotonation of the bound substrate and desolvation of substrate and cofactor in the rate-determining step.
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| 7. |
- Jensen, Kasper, et al.
(författare)
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How O-2 binds to heme - Reasons for rapid binding and spin inversion
- 2004
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Ingår i: Journal of Biological Chemistry. - 1083-351X. ; 279:15, s. 14561-14569
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Tidskriftsartikel (refereegranskat)abstract
- We have used density functional methods to calculate fully relaxed potential energy curves of the seven lowest electronic states during the binding of O-2 to a realistic model of ferrous deoxyheme. Beyond a Fe-O distance of similar to 2.5 Angstrom, we find a broad crossing region with five electronic states within 15 kJ/mol. The almost parallel surfaces strongly facilitate spin inversion, which is necessary in the reaction of O-2 with heme ( deoxyheme is a quintet and O-2 a triplet, whereas oxyheme is a singlet). Thus, despite a small spin-orbit coupling in heme, the transition probability approaches unity. Using reasonable parameters, we estimate a transition probability of 0.06-1, which is at least 15 times larger than for the nonbiological Fe-O+ system. Spin crossing is anticipated between the singlet ground state of bound oxyheme, the triplet and septet dissociation states, and a quintet intermediate state. The fact that the quintet state is close in energy to the dissociation couple is of biological importance, because it explains how both spin states of O-2 may bind to heme, thereby increasing the overall efficiency of oxygen binding. The activation barrier is estimated to be < 15 kJ/mol based on our results and Mossbauer experiments. Our results indicate that both the activation energy and the spin-transition probability are tuned by the porphyrin as well as by the choice of the proximal heme ligand, which is a histidine in the globins. Together, they may accelerate O-2 binding to iron by &SIM;10(11) compared with the Fe-O+ system. A similar near degeneracy between spin states is observed in a ferric deoxyheme model with the histidine ligand hydrogen bonded to a carboxylate group, i.e. a model of heme peroxidases, which bind H2O2 in this oxidation state.
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| 8. |
- Jensen, Kasper, et al.
(författare)
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How the Co-C bond is cleaved in coenzyme B-12 enzymes: A theoretical study
- 2005
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 1520-5126 .- 0002-7863. ; 127:25, s. 9117-9128
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Tidskriftsartikel (refereegranskat)abstract
- The homolytic cleavage of the organometallic Co-C bond in vitamin B-12-dependent enzymes is accelerated by a factor of similar to 10(12) in the protein compared to that of the isolated cofactor in aqueous solution. To understand this much debated effect, we have studied the Co-C bond cleavage in the enzyme glutamate mutase with combined quantum and molecular mechanics methods. We show that the calculated bond dissociation energy (BDE) of the Co-C bond in adenosyl cobalamin is reduced by 135 kJ/mol in the enzyme. This catalytic effect can be divided into four terms. First, the adenosine radical is kept within 4.2 angstrom of the Cc ion in the enzyme, which decreases the BDE by 20 kJ/mol. Second, the surrounding enzyme stabilizes the dissociated state by 42 kJ/mol using electrostatic and van der Waals interactions. Third, the protein itself is stabilized by 11 kJ/mol in the dissociated state. Finally, the coenzyme is geometrically distorted by the protein, and this distortion is 61 kJ/mol larger in the Co-III state. This deformation of the coenzyme is caused mainly by steric interactions, and it is especially the ribose moiety and the Co-C5'-C4' angle that are distorted. Without the polar ribose group, the catalytic effect is much smaller, e.g. only 42 kJ/mol for methyl cobalamin. The deformation of the coenzyme is caused mainly by the substrate, a side chain of the coenzyme itself, and a few residues around the adenosine part of the coenzyme.
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| 9. |
- Jensen, Kasper, et al.
(författare)
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Importance of proximal hydrogen bonds in haem proteins.
- 2003
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Ingår i: Molecular Physics. - : Informa UK Limited. - 1362-3028 .- 0026-8976. ; 101:13, s. 2003-2018
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Tidskriftsartikel (refereegranskat)abstract
- We have used the density functional B3LYP method to study the effect of hydrogen bonds from the histidine ligand in various haem proteins to carboxyl groups or to the carbonyl backbone. Hydrogen bonds to carbonyl groups (encountered in globins and cytochromes, for example) have a small influence on the geometry and properties of the haem site. However, hydrogen bonds to a carboxyl group (encountered in peroxidases and haem oxidase) may have a profound effect. The results indicate that in the Fe3+ state, this leads to a deprotonation of the histidine ligand, whereas in the Fe2+ state, the proton involved in the hydrogen bond may reside on either histidine or the carboxylate group, depending on the detailed structure of the surroundings. If the histidine is deprotonated, the axial Fe-N bond length decreases by 0.15 Å, whereas the equatorial bond lengths increase. Moreover, the charge on iron and histidine is reduced, as is the spin density on iron. Most importantly, the energy difference between the high and intermediate spin states changes so that whereas the two spin states are degenerate in the Fe2+ state for the protonated histidine, they are degenerate for the Fe3+ state when it is deprotonated. This may facilitate the spin-forbidden binding of dioxygen and peroxide substrates, which takes place for the Fe2+ state in globins but in the Fe3+ state in peroxidases. The reduction potential of the haem group decreases when it hydrogen-bonds to a negatively charged group. The inner-sphere reorganization energy of the Fe2+/Fe3+ transition in a five-coordinate haem complex is ˜30 kJ mol−1, except when the histidine ligand is deprotonated without any hydrogen-bond interaction.
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| 10. |
- Jensen, Kasper, et al.
(författare)
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O2-binding to heme: electronic structure and spectrum of oxyheme, studied by multiconfigurational methods
- 2005
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Ingår i: Journal of Inorganic Biochemistry. - : Elsevier BV. - 1873-3344 .- 0162-0134. ; 99:1, s. 45-54
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Tidskriftsartikel (refereegranskat)abstract
- We have studied the ground state of a realistic model of oxyheme with multiconfigurational second-order perturbation theory (CASPT2). Our results show that the ground-state electronic structure is strongly multiconfigurational in character. Thus, the wavefunction is a mixture of many different configurations, of which the three most important ones are approximately 1FeII–1O2 (70%), (12%) and 3FeII–3O2 (3%). Thus, the wavefunction is dominated by closed-shell configurations, as suggested by Pauling, whereas the Weiss configuration is not encountered among the 10 most important configurations. However, many other states are also important for this multiconfigurational wavefunction. Moreover, the traditional view is based on an oversimplified picture of the atomic-orbital contributions to the molecular orbitals. Thus, the population analysis indicates that all five iron orbitals are significantly occupied (by 0.5–2.0 electrons) and that the total occupation is most similar to the 3FeII–3O2 picture. The net charge on O2 is small, −0.20 e. Thus, it is quite meaningless to discuss which is the best valence-bond description of this inherently multiconfigurational system. Finally, we have calculated the eleven lowest ligand-field excited states of oxyheme and assigned the experimental spectrum of oxyhemoglobin with an average error of 0.24 eV.
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