Linked Life Data

3504965

Source:http://linkedlifedata.com/resource/pubmed/id/3504965

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
3
pubmed:dateCreated
1989-2-9
pubmed:abstractText
The conformation of the immunosuppressive drug cyclosporin A (CPA), both in apolar solution and in crystalline state, has been studied by computer simulation techniques. Three molecular dynamics (MD) simulations have been performed: one modelling the crystal structure and two modelling the structure in apolar solution, using a restrained MD approach in which data from nuclear magnetic resonance (NMR) and infrared (IR) spectroscopy are taken into account. The simulation of the crystalline state (MDC) concerns a system of 4 unit cells containing 16 cyclosporin A molecules and 22 water molecules, which is simulated using crystalline periodic boundary conditions. The simulations modelling the apolar solvent conformation (MDS) concern one isolated cyclosporin A molecule. In these simulations an extra term in the interatomic potential function is used, which forces the molecule to satisfy a set of 57 atom-atom distance constraints originating from nuclear Overhauser effects (NOEs) obtained from NMR spectroscopy and one distance constraint deduced from IR spectroscopy. From a comparison of the results of the crystal simulation to those of the X-ray experiment in terms of structure, atomic fluctuations, hydrogen bond pattern, etc., it is concluded that the force field that is used yields an adequate representation of crystalline cyclosporin A. Secondly, it is shown that the dynamic modelling technique that is used to obtain a structure in a polar solution from NMR distance information works well. Starting from initial conformations which have a root mean square difference of 0.14 nm both distance restrained MD simulations converge to the same final solution structure. A comparison of the crystal structure of cyclosporin A and the one in apolar solution shows that there are significant differences. The overall difference in atomic positions is 0.09 nm for the C alpha atoms and 0.17 nm for all atoms. In apolar solution, the molecule is slightly more bent and the side chains of 1 MeBmt and 10 MeLeu adopt a different conformation.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Oct
pubmed:issn
0920-654X
pubmed:author
pubmed:issnType
Print
pubmed:volume
1
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
219-41
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed:year
1987
pubmed:articleTitle
Molecular dynamics simulations of cyclosporin A: the crystal structure and dynamic modelling of a structure in apolar solution based on NMR data.
pubmed:affiliation
Institut für Organische Chemie, J.-W.-Goethe-Universitat, Frankfurt, F.R.G.
pubmed:publicationType
Journal Article, Comparative Study, Research Support, Non-U.S. Gov't