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

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...

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Autores principales: Chillemi, Giovanni, Bruselles, Alessandro, Fiorani, Paola, Bueno, Susana, Desideri, Alessandro
Formato: Texto
Lenguaje:English
Publicado: Oxford University Press 2007
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1888835/
https://www.ncbi.nlm.nih.gov/pubmed/17439970
http://dx.doi.org/10.1093/nar/gkm199
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author Chillemi, Giovanni
Bruselles, Alessandro
Fiorani, Paola
Bueno, Susana
Desideri, Alessandro
author_facet Chillemi, Giovanni
Bruselles, Alessandro
Fiorani, Paola
Bueno, Susana
Desideri, Alessandro
author_sort Chillemi, Giovanni
collection PubMed
description 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 Å, the catalytic pentad remains preassembled, the largest deviation of the active site backbone atoms from the starting crystallographic structure being only 1.7 Å. 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.
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spelling pubmed-18888352007-06-22 The open state of human topoisomerase I as probed by molecular dynamics simulation Chillemi, Giovanni Bruselles, Alessandro Fiorani, Paola Bueno, Susana Desideri, Alessandro Nucleic Acids Res Structural Biology 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 Å, the catalytic pentad remains preassembled, the largest deviation of the active site backbone atoms from the starting crystallographic structure being only 1.7 Å. 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. Oxford University Press 2007-05 2007-04-16 /pmc/articles/PMC1888835/ /pubmed/17439970 http://dx.doi.org/10.1093/nar/gkm199 Text en © 2007 The Author(s) This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Structural Biology
Chillemi, Giovanni
Bruselles, Alessandro
Fiorani, Paola
Bueno, Susana
Desideri, Alessandro
The open state of human topoisomerase I as probed by molecular dynamics simulation
title The open state of human topoisomerase I as probed by molecular dynamics simulation
title_full The open state of human topoisomerase I as probed by molecular dynamics simulation
title_fullStr The open state of human topoisomerase I as probed by molecular dynamics simulation
title_full_unstemmed The open state of human topoisomerase I as probed by molecular dynamics simulation
title_short The open state of human topoisomerase I as probed by molecular dynamics simulation
title_sort open state of human topoisomerase i as probed by molecular dynamics simulation
topic Structural Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1888835/
https://www.ncbi.nlm.nih.gov/pubmed/17439970
http://dx.doi.org/10.1093/nar/gkm199
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