The open state of human topoisomerase I as probed by molecular dynamics simulation.

Abstract:

:The open state of human topoisomerase I has been probed by molecular dynamics simulation, starting from the coordinates of the closed structure of the protein complexed with DNA, after elimination of the 22-bp DNA duplex oligonucleotide. A repulsion force between the two lips of the protein has been introduced for a short time to induce destabilization of the local minimum, after which an unperturbed simulation has been carried out for 10 ns. The simulation shows that the protein undergoes a large conformational change due to rearrangements in the orientation of the protein domains, which however move as a coherent unit, fully maintaining their secondary and tertiary structures. Despite movements between the domains as large as 80-90 A, the catalytic pentad remains preassembled, the largest deviation of the active site backbone atoms from the starting crystallographic structure being only 1.7 A. Electrostatic calculation of the open protein structure shows that the protein displays a vast positive region with the active site residues located nearly at its center, in a conformation perfectly suited to interact with the negatively charged supercoiled DNA substrate.

journal_name

Nucleic Acids Res

journal_title

Nucleic acids research

authors

Chillemi G,Bruselles A,Fiorani P,Bueno S,Desideri A

doi

10.1093/nar/gkm199

subject

Has Abstract

pub_date

2007-01-01 00:00:00

pages

3032-8

issue

9

eissn

0305-1048

issn

1362-4962

pii

gkm199

journal_volume

35

pub_type

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