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Biomedical subjects

B Norden

Publications and source records attributed to B Norden.

12 recordsLinked to original sources
PubMed2001

Computational modelling of inhibitor binding to human thrombin.

Thrombin is an essential protein involved in blood clot formation and an important clinical target, since disturbances of the coagulation process cause serious cardiovascular diseases such as thrombosis. Here we evaluate the performance of a molecular dynamics based method for predicting the binding affinities of different types of human thrombin inhibitors. For a series of eight ligands the method ranks their relative affinities reasonably well. The binding free energy difference between high and low affinity representatives in the test set is quantitatively reproduced, as well as the stereospecificity for a chiral inhibitor. The original parametrisation of this linear interaction energy method requires the addition of a constant energy term in the case of thrombin. This yields a mean unsigned error of 0.68 kcal/mol for the absolute binding free energies. This type of approach is also useful for elucidating three-dimensional structure-activity relationships in terms of microscopic interactions of the ligands with the solvated enzyme.

Antithrombins↗
PubMed2000

Agro-predation: usurpation of attine fungus gardens by Megalomyrmex ants.

A new ant species of Megalomyrmex conducts mass raids to usurp gardens of the fungus-growing ant Cyphomyrmex longiscapus, then lives in the gardens and consumes the cultivated fungus. Unlike attine ants, however, Megalomyrmex sp. does not forage for substrate to manure the gardens; therefore, when gardens become depleted, Megalomyrmex sp. must locate and usurp new gardens. Megalomyrmex sp. workers feed their larvae with attine brood, but only after removing the fungal mycelium that covers the attine larval integument, suggesting that this fungal coat may provide partial protection against other predators. Unlike other known Megalomyrmex species, which coexist as social parasites in attine colonies, Megalomyrmex sp. expels its attine hosts during the garden raids. Megalomyrmex sp. thus maintains a unique agro-predatory lifestyle that is described here for the first time.

Aggression↗
PubMed1994

Flow linear dichroism and electron microscopic analysis of protein-DNA complexes of a mutant UvrB protein that binds to but cannot kink DNA.

(A)BC excinuclease of Escherichia coli is the enzymatic activity resulting from sequential and partially overlapping actions of UvrA, UvrB, and UvrC protein. UvrA is a molecular matchmaker which promotes the formation of a stable UvrB-damaged DNA complex in which the DNA is kinked by about 130 degrees. The UvrB-DNA complex is then recognized by UvrC and two incisions are made in the DNA by the joint actions of UvrC and UvrB. A mutant of UvrB (D478A) can be loaded onto the DNA but it does not interact with UvrC to cause a nick 3' to the lesion. Based on the lack of a DNase-I-hypersensitive site in the footprint of the mutant, it was proposed that the lack of incision was due to the inability of the mutant UvrB to kink the DNA. In the current study we have investigated the interaction of the mutant UvrB with DNA using two biophysical methods, flow linear dichroism and electron microscopy. Both methods reveal that the mutant UvrB is unable to bend DNA.

Adenosine Triphosphatases↗
PubMed1993

PNA hybridizes to complementary oligonucleotides obeying the Watson-Crick hydrogen-bonding rules.

DNA analogues are currently being intensely investigated owing to their potential as gene-targeted drugs. Furthermore, their properties and interaction with DNA and RNA could provide a better understanding of the structural features of natural DNA that determine its unique chemical, biological and genetic properties. We recently designed a DNA analogue, PNA, in which the backbone is structurally homomorphous with the deoxyribose backbone and consists of N-(2-aminoethyl)glycine units to which the nucleobases are attached. We showed that PNA oligomers containing solely thymine and cytosine can hybridize to complementary oligonucleotides, presumably by forming Watson-Crick-Hoogsteen (PNA)2-DNA triplexes, which are much more stable than the corresponding DNA-DNA duplexes, and bind to double-stranded DNA by strand displacement. We report here that PNA containing all four natural nucleobases hybridizes to complementary oligonucleotides obeying the Watson-Crick base-pairing rules, and thus is a true DNA mimic in terms of base-pair recognition.

Base Sequence↗
PubMed1989

Electric and flow linear dichroism of unfolded and condensed chromatin: a comparative study at low and intermediate ionic strength.

Identical samples containing polynucleosomal chains of chicken erythrocyte (CE) and Ehrlich ascites tumour (EA) chromatin were studied under various ionic conditions with regard to electric linear dichroism (ELD) and flow linear dichroism (FLD). Both orientation techniques consistently confirmed that, in the limit of very low ionic strength and in the absence of multivalent cations, the reduced linear dichroism of chromatin is negative in the DNA-base absorption band, as expected for an extended zig-zag polynucleosomal conformation. With increasing electrolyte content, both ELD and FLD decreased drastically in amplitude, but in contrast to the ELD which remains negative in an intermediate range of low ionic strength (0.1-0.5 mM Mg2+) the FLD changes sign and becomes positive. The ELD and FLD amplitudes decrease with higher Mg2+ concentrations and FLD even vanishes in the region of 0.2-0.4 mM; both signals are positive above 0.4-0.5 mM Mg2+. The origin of the dissimilarities between ELD and FLD observations is still not fully understood. Several possibilities are considered: ELD signals are more influenced than FLD by the presence of short chromatin chains, nucleosomes and small pieces of naked DNA, while FLD is more susceptible to the presence of large, easily orientable, scattering aggregates. Different preferred orientation directions of the chromatin fibre with respect to electric and hydrodynamic fields may also be involved. Finally, FLD and ELD probably "see" different features of the chromatin structure.

Animals↗
PubMed1988

Molecular flexibility of extended and compacted polynucleosomes. A steady-state fluorescence polarization study.

We have studied the effects of Na+ (5-120 mM) and Mg2+ (0-6 mM) on the internal and overall flexibility of polynucleosome fragments from nuclease-solubilized chromatin from Ehrlich ascites cells. The mobility was monitored by the steady-state fluorescence polarization of the intercalated ethidium cation. The internal polynucleosome flexibility decreases continuously as the extended chromatin fragments are being compacted at increasing salt concentrations, and it can be further suppressed at ionic strengths above those where the 30 nm fiber is formed. The effect may be visualized as an initial formation of a loose 30 nm fiber that is further compacted at increasing ionic strengths. We observe several differences in the effects of Na+ and Mg2+ upon chromatin compaction. First, chromatin compacted by Mg2+ is less flexible than that compacted by Na+, suggesting a "tighter" chromatin structure with Mg2+. Second, Mg2+ affects the internal mobility in polynucleosome fragments shorter than 6-7 nucleosomes, which are too short to be compacted with Na+. Third, Mg2+ causes extensive macroscopic aggregation at concentrations above 0.2-0.3 mM, but the aggregation is uncorrelated with the intramolecular compaction. A quantitative evaluation of the overall polynucleosome "tumbling" mobility indicates that the compacted fragments possess more internal flexibility than do corresponding high molecular weight chromatin fibers. Finally, we note a correlation between the ethidium binding constant and the internal chromatin flexibility, possibly arising from lower torsional and "unwinding" flexibility of the linker DNA segments of compacted chromatin fibers.

Animals↗
PubMed1986

A 13C-NMR study of mutant hemoglobins with altered oxygen affinity.

The 13CO-NMR spectra of carbonylhemoglobins Saint Mandé (beta 102Asn----Tyr), Malmö (beta 97His----Gln), Hôtel Dieu (beta 99Asp----Gly) and Ao have been determined. The positions of the 13CO resonances for hemoglobins Ao, Malmö and Hôtel Dieu were similar indicating similar ligand environments for all. The 13CO resonance for the beta-subunit of Saint Mandé was upfield-shifted compared to the others. This is evidence that structural changes at the beta 102 position directly affect iron-ligand bonding as well as quaternary structure.

Carbon Isotopes↗