Biomedical subjects

Kasper P Jensen

Publications and source records attributed to Kasper P Jensen.

11 recordsLinked to original sources

PubMed2007

Performance of density functionals for first row transition metal systems.

This article investigates the performance of five commonly used density functionals, B3LYP, BP86, PBE0, PBE, and BLYP, for studying diatomic molecules consisting of a first row transition metal bonded to H, F, Cl, Br, N, C, O, or S. Results have been compared with experiment wherever possible. Open-shell configurations are found more often in the order PBE0>B3LYP>PBE approximately BP86>BLYP. However, on average, 58 of 63 spins are correctly predicted by any functional, with only small differences. BP86 and PBE are slightly better for obtaining geometries, with errors of only 0.020 A. Hybrid functionals tend to overestimate bond lengths by a few picometers and underestimate bond strengths by favoring open shells. Nonhybrid functionals usually overestimate bond energies. All functionals exhibit similar errors in bond energies, between 42 and 53 kJmol. Late transition metals are found to be better modeled by hybrid functionals, whereas nonhybrid functionals tend to have less of a preference. There are systematic errors in predicting certain properties that could be remedied. BLYP performs the best for ionization potentials studied here, PBE0 the worst. In other cases, errors are similar. Finally, there is a clear tendency for hybrid functionals to give larger dipole moments than nonhybrid functionals. These observations may be helpful in choosing and improving existing functionals for tasks involving transition metals, and for designing new, improved functionals.

Journal Article↗

PubMed2006

The role of axial ligands for the structure and function of chlorophylls.

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.

Amino Acids↗

PubMed2006

Iron-sulfur clusters: why iron?

This communication addresses a simple question by means of density functional calculations: Why is iron used as the metal in iron-sulfur clusters? While there may be several answers to this question, it is shown here that one feature - the well-defined inner-sphere reorganization energy of self-exchange electron transfer - is very much favored in iron-sulfur clusters as opposed to metal substituted analogues of Mn, Co, Ni, and Cu. Furthermore, the conclusion holds for both 1Fe and 2Fe type iron-sulfur clusters. The results show that only iron provides a small inner-sphere reorganization energy of 21 kJ/mol in 1Fe (rubredoxin) and 46 kJ/mol in 2Fe (ferredoxin) models, whereas other metal ions exhibit values in the range 57-135 kJ/mol (1Fe) and 94-140 kJ/mol (2Fe). This simple result provides an important, although partial, explanation why iron alone is used in this type of clusters. The results can be explained by simple orbital rules of electron transfer, which state that the occupation of anti-bonding orbitals should not change during the redox reactions. This rule immediately suggests good and poor electron carriers.

Algorithms↗

PubMed2006

The reaction mechanism of iron and manganese superoxide dismutases studied by theoretical calculations.

We have studied the detailed reaction mechanism of iron and manganese superoxide dismutase with density functional calculations on realistic active-site models, with large basis sets and including solvation, zero-point, and thermal effects. The results indicate that the conversion of O2- to O2 follows an associative mechanism, with O2- directly binding to the metal, followed by the protonation of the metal-bound hydroxide ion, and the dissociation of 3O2. All these reaction steps are exergonic. Likewise, we suggest that the conversion of O2- to H2O2 follows an at least a partly second-sphere pathway. There are small differences in the preferred oxidation and spin states, as well as in the geometries, of Fe and Mn, but these differences have little influence on the energetics, and therefore on the reaction mechanism of the two types of superoxide dismutases. For example, the two metals have very similar reduction potentials in the active-site models, although they differ by 0.7 V in water solution. The reaction mechanisms and spin states seem to have been designed to avoid spin conversions or to facilitate them by employing nearly degenerate spin states.

Binding Sites↗

PubMed2005

How the Co-C bond is cleaved in coenzyme B12 enzymes: a theoretical study.

The homolytic cleavage of the organometallic Co-C bond in vitamin B12-dependent enzymes is accelerated by a factor of approximately 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 angstroms of the Co 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.

Carbon↗

PubMed2005

Electronic structure of Cob(I)alamin: the story of an unusual nucleophile.

The electronic structure and the ligand-field spectrum of cobalt(I) corrin is reported using complete active space multiconfigurational perturbation theory (CASPT2) to address some inconsistencies and the nature of the cobalt(I) "supernucleophile", cob(I)alamin. An assignment of six of the seven intense lines in the experimental spectrum is obtained at a root-mean-square accuracy of 0.14 eV and largest error of 0.21 eV. Agreement is significantly better for CASPT2 than density functional theory (DFT), but DFT does surprisingly well. The correlated wave function implies that the ground state of Co(I) corrin is severely multiconfigurational, with only 67% of the d(8) reference configuration and prominent contributions of 20% from open-shell metal-to-ligand charge-transfer configurations. The ground state exhibits a fascinating degree of covalency between cobalt and the nitrogen orbitals, described by the bonding and antibonding orbital pair of a cobalt d-orbital and a delta-orbital linearly combined from nitrogen orbitals. Thus, the standard description of the d(8) supernucleophile is not completely valid. From a biological perspective, the mixing in of Co(II) configurations in cob(I)alamin may be an important reason for the redox accessibility of the formal Co(I) state of the cofactor, which again provides the catalytic power for one half-reaction of enzymes such as cobalamin-dependent methionine synthase.

Models, Molecular↗

PubMed2005

O2-binding to heme: electronic structure and spectrum of oxyheme, studied by multiconfigurational methods.

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%), FeIV-2O2(2-) (12%) and 3FeII-3O2 (3%). Thus, the wavefunction is dominated by closed-shell configurations, as suggested by Pauling, whereas the Weiss 2FeIII-2O2- 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.

Electrons↗

PubMed2004

How O2 binds to heme: reasons for rapid binding and spin inversion.

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 approximately 2.5 A, 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 Mössbauer 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 approximately 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 H(2)O(2) in this oxidation state.

Electrons↗

PubMed2003

Conversion of homocysteine to methionine by methionine synthase: a density functional study.

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.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗

PubMed2003

Comparison of the chemical properties of iron and cobalt porphyrins and corrins.

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 M(II/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 M(II) complexes with an imidazole ligand and four-coordinate M(I/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 Co(III), Co(II), and Co(I) 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 [Co(I)Cor] is more easily formed (by at least 40 kJ mole(-1)) than [Fe(I)Por]. Cobalt and corrin form a strong Cobond;C bond that is more stable against hydrolysis than iron and porphine. Finally, Fe(II/III) gives a much lower reorganisation energy than Co(II/III); this is owing to the occupied d(z2) orbital in Co(II). Altogether, these results give some clues about how nature has chosen the tetrapyrrole rings and their central metal ion.

Cobalt↗

PubMed2003

Metal ion enhanced binding of AMD3100 to Asp262 in the CXCR4 receptor.

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: Cu(2+), Zn(2+), or Ni(2+) 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 Cu(2+) or Ni(2+) 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 Asp(171) and Asp(262), the enhancing effect of the metal ion was selectively eliminated by substitution of Asp(262) 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 Asp(262). 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.

Amino Acid Sequence↗