| Autor: |
Dolenc J; Laboratory of Biomolecular Research, Division of Biology and Chemistry , Paul Scherrer Institut , CH-5232 Villigen , Switzerland., van Gunsteren WF; Laboratory of Physical Chemistry , Swiss Federal Institute of Technology, ETH , CH-8093 Zurich , Switzerland., Prota AE; Laboratory of Biomolecular Research, Division of Biology and Chemistry , Paul Scherrer Institut , CH-5232 Villigen , Switzerland., Steinmetz MO; Laboratory of Biomolecular Research, Division of Biology and Chemistry , Paul Scherrer Institut , CH-5232 Villigen , Switzerland.; University of Basel, Biozentrum , CH-4056 Basel , Switzerland., Missimer JH; Laboratory of Biomolecular Research, Division of Biology and Chemistry , Paul Scherrer Institut , CH-5232 Villigen , Switzerland. |
| Abstrakt: |
Epothilones are among the most potent chemotherapeutic drugs used for the treatment of cancer. Epothilone A (EpoA), a natural product, is a macrocyclic molecule containing 34 non-hydrogen atoms and a thiazole side chain. NMR studies of EpoA in aqueous solution, unbound as well as bound to αβ-tubulin, and unbound in dimethyl sulfoxide (DMSO) solution have delivered sets of nuclear Overhauser effect (NOE) atom-atom distance bounds, but no structures based on NMR data are present in structural data banks. X-ray diffraction of crystals has provided structures of EpoA unbound and bound to αβ-tubulin. Since both crystal structures derived from X-ray diffraction intensities do not completely satisfy the three available sets of NOE distance bounds for EpoA, molecular dynamics (MD) simulations have been employed to obtain conformational ensembles in aqueous and in DMSO solution that are compatible with the respective NOE data. It was found that EpoA displays a larger conformational variability in DMSO than in water and the two conformational ensembles show little overlap. Yet, they both provide conformational scaffolds that are energetically accessible at physiological temperature and pressure. |
