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Role of the Linker Domain and the 203–214 N-Terminal Residues in the Human Topoisomerase I DNA Complex Dynamics

G. Chillemi ^*, M. Redinbo , A. Bruselles ^*  and A. Desideri 

^* CASPUR, Consortium for Supercomputing in Research, Via dei Tizii 6b, Rome, Italy; Department of Chemistry, Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, North Carolina; and INFM and Department of Biology, University of Rome "Tor Vergata", Via della Ricerca Scientifica, Rome, Italy

Correspondence: Address reprint requests to A. Desideri, Dept. of Biology, University of Rome Tor Vergata, Via della Ricerca Scientifica, 00133 Rome, Italy. Tel.: 39-06-72594376; Fax: 39-06-72594326; E-mail: desideri{at}uniroma2.it.

The influence of the N-terminal residues 203–214 and the linker domain on motions in the human topoisomerase I-DNA complex has been investigated by comparing the molecular dynamics simulations of the system with (topo70) or without (topo58/6.3) these regions. Topo58/6.3 is found to fluctuate more than topo70, indicating that the presence of the N-terminal residues and the linker domain dampen the core and C-terminal fluctuations. The simulations also show that residues 203–207 and the linker domain participate in a network of correlated movements with key regions of the enzyme, involved in the human topoisomerase I catalytic cycle, providing a structural-dynamical explanation for the better DNA relaxation activity of topo70 when compared to topo58/6.3. The data have been examined in relation to a wealth of biochemical, site-directed mutagenesis and crystallographic data on human topoisomerase I. The simulations finally show the occurrence of a network of direct and water mediated hydrogen bonds in the proximity of the active site, and the presence of a water molecule in the appropriate position to accept a proton from the catalytic Tyr-723 residue, suggesting that water molecules have an important role in the stabilization and function of this enzyme.

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