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Biophys J, July 2001, p. 490-500, Vol. 81, No. 1

Structure and Hydration of the DNA-Human Topoisomerase I Covalent Complex

Giovanni Chillemi,* Tiziana Castrignanò,* and Alessandro Desideridagger

 *CASPUR, c/o University of Rome "La Sapienza," 00185; and  dagger INFM and Department of Biology, University of Rome "Tor Vergata," 00133 Rome, Italy

The structure and hydration of reconstituted human topoisomerase I comprising the core and the carboxyl-terminal domains in covalent complex with 22-basepair DNA duplex has been investigated by molecular dynamics simulation. The structure and the intermolecular interactions were found to be well maintained over the simulation. The complex displays a high degree of flexibility of the contact area, confirmed by the presence of numerous water-mediated protein-DNA hydrogen bonds comparable in quantity and distribution to the direct ones. The interaction between the enzyme and the solvent also provides the key for interpreting the experimental reduction of activity or affinity observed upon single residue mutation. Finally, four long lasting water molecules are observed in the proximity of the active site, one of which in the appropriate position to accept a proton from the active Tyr723.

Biophys J, July 2001, p. 490-500, Vol. 81, No. 1
© 2001 by the Biophysical Society   0006-3495/01/07/490/11  $2.00


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