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Structure and dynamics of dioxygen bound to cobalt and iron heme.

ABSTRACT: In this study we use ab initio molecular dynamics simulations to analyze the structure and dynamics of the oxygen ligand in models of the oxymyoglobin active site and its cobalt-substituted analog. Our calculations are performed for iron-porphyrin and cobalt-porphyrin complexes with imidazole and oxygen as axial ligands, and we investigate the effect of the distal histidine in the structure and dynamics of the metal-oxygen unit (MeO(2), Me = Fe, Co). We find that the interaction between the distal histidine and the oxygen ligand is stronger for the cobalt complex than for the iron one, consistent with the superoxide ion character of the bound O(2). The dynamics of the O(2) ligand can be described as oscillations of the O-O axis projection on the porphyrin plane within a porphyrin quadrant combined with frequent jumps from one quadrant to another. However, the ligand motion is significantly faster for CoO(2) compared to FeO(2). As a result, the iron complex shows localized ligand sites, whereas for cobalt several configurations are possible. This gives support to the highly dynamic motion of the oxygen ligand found in several experiments on cobalt oxymyoglobin and model complexes and underlines the higher mobility of the CoO(2) fragment compared to FeO(2).

SUBMITTER: Degtyarenko I

PROVIDER: S-EPMC1557552 | biostudies-literature | 2006 Sep

REPOSITORIES: biostudies-literature

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Structure and dynamics of dioxygen bound to cobalt and iron heme.

Degtyarenko Ivan I Nieminen Risto M RM Rovira Carme C

Biophysical journal 20060602 6

In this study we use ab initio molecular dynamics simulations to analyze the structure and dynamics of the oxygen ligand in models of the oxymyoglobin active site and its cobalt-substituted analog. Our calculations are performed for iron-porphyrin and cobalt-porphyrin complexes with imidazole and oxygen as axial ligands, and we investigate the effect of the distal histidine in the structure and dynamics of the metal-oxygen unit (MeO(2), Me = Fe, Co). We find that the interaction between the dist ...[more]

PMID: 16751243

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Project description:The nature of the ligand is an important aspect of controlling the structure and reactivity in coordination chemistry. In connection with our study of heme-copper-oxygen reactivity relevant to cytochrome c oxidase dioxygen-reduction chemistry, we compare the molecular and electronic structures of two high-spin heme-peroxo-copper [Fe(III)O(2)(2-)Cu(II)](+) complexes containing N(4) tetradentate (1) or N(3) tridentate (2) copper ligands. Combining previously reported and new resonance Raman and EXAFS data coupled to density functional theory calculations, we report a geometric structure and more complete electronic description of the high-spin heme-peroxo-copper complexes 1 and 2, which establish mu-(O(2)(2-)) side-on to the Fe(III) and end-on to Cu(II) (mu-eta(2):eta(1)) binding for the complex 1 but side-on/side-on (mu-eta(2):eta(2)) mu-peroxo coordination for the complex 2. We also compare and summarize the differences and similarities of these two complexes in their reactivity toward CO, PPh(3), acid, and phenols. The comparison of a new X-ray structure of mu-oxo complex 2a with the previously reported 1a X-ray structure, two thermal decomposition products respectively of 2 and 1, reveals a considerable difference in the Fe-O-Cu angle between the two mu-oxo complexes ( angleFe-O-Cu = 178.2 degrees in 1a and angleFe-O-Cu = 149.5 degrees in 2a). The reaction of 2 with 1 equiv of an exogenous nitrogen-donor axial base leads to the formation of a distinctive low-temperature-stable, low-spin heme-dioxygen-copper complex (2b), but under the same conditions, the addition of an axial base to 1 leads to the dissociation of the heme-peroxo-copper assembly and the release of O(2). 2b reacts with phenols performing H-atom (e(-) + H(+)) abstraction resulting in O-O bond cleavage and the formation of high-valent ferryl [Fe(IV)=O] complex (2c). The nature of 2c was confirmed by a comparison of its spectroscopic features and reactivity with those of an independently prepared ferryl complex. The phenoxyl radical generated by the H-atom abstraction was either (1) directly detected by electron paramagnetic resonance spectroscopy using phenols that produce stable radicals or (2) indirectly detected by the coupling product of two phenoxyl radicals.

Project description:Deciphering gene regulatory mechanisms through the analysis of high-throughput expression data is a challenging computational problem. Previous computational studies have used large expression datasets in order to resolve fine patterns of coexpression, producing clusters or modules of potentially coregulated genes. These methods typically examine promoter sequence information, such as DNA motifs or transcription factor occupancy data, in a separate step after clustering. We needed an alternative and more integrative approach to study the oxygen regulatory network in Saccharomyces cerevisiae using a small dataset of perturbation experiments. Mechanisms of oxygen sensing and regulation underlie many physiological and pathological processes, and only a handful of oxygen regulators have been identified in previous studies. We used a new machine learning algorithm called MEDUSA to uncover detailed information about the oxygen regulatory network using genome-wide expression changes in response to perturbations in the levels of oxygen, heme, Hap1, and Co2+. MEDUSA integrates mRNA expression, promoter sequence, and ChIP-chip occupancy data to learn a model that accurately predicts the differential expression of target genes in held-out data. We used a novel margin-based score to extract significant condition-specific regulators and assemble a global map of the oxygen sensing and regulatory network. This network includes both known oxygen and heme regulators, such as Hap1, Mga2, Hap4, and Upc2, as well as many new candidate regulators. MEDUSA also identified many DNA motifs that are consistent with previous experimentally identified transcription factor binding sites. Because MEDUSA's regulatory program associates regulators to target genes through their promoter sequences, we directly tested the predicted regulators for OLE1, a gene specifically induced under hypoxia, by experimental analysis of the activity of its promoter. In each case, deletion of the candidate regulator resulted in the predicted effect on promoter activity, confirming that several novel regulators identified by MEDUSA are indeed involved in oxygen regulation. MEDUSA can reveal important information from a small dataset and generate testable hypotheses for further experimental analysis.

Dataset Information

Structure and dynamics of dioxygen bound to cobalt and iron heme.

Publications

Structure and dynamics of dioxygen bound to cobalt and iron heme.

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