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Computationally enhanced X-ray diffraction analysis of a gold(III) complex interacting with the human telomeric DNA G-quadruplex. Unravelling non-unique ligand positioning

Cirri, Damiano ; Bazzicalupi, Carla ; Ryde, Ulf LU orcid ; Bergmann, Justin LU ; Binacchi, Francesca ; Nocentini, Alessio ; Pratesi, Alessandro ; Gratteri, Paola and Messori, Luigi (2022) In International Journal of Biological Macromolecules 211. p.506-513
Abstract

The crystal structure of the human telomeric DNA Tel24 G-quadruplex (Tel24 = TAG3(T2AG3)3T) in complex with the novel [AuL] species (with L = 2,4,6-tris(2-pyrimidyl)-1,3,5-triazine - TPymT-α) was solved by a novel joint molecular mechanical (MM)/quantum mechanical (QM) innovative approach. The quantum-refinement crystallographic method (crystallographic refinement enhanced with quantum mechanical calculation) was adapted to treat the [AuL]/G-quadruplex structure, where each gold complex in the binding site was found spread over four equally occupied positions. The four positions were first determined by docking restrained to the crystallographically determined metal ions' coordinates. Then,... (More)

The crystal structure of the human telomeric DNA Tel24 G-quadruplex (Tel24 = TAG3(T2AG3)3T) in complex with the novel [AuL] species (with L = 2,4,6-tris(2-pyrimidyl)-1,3,5-triazine - TPymT-α) was solved by a novel joint molecular mechanical (MM)/quantum mechanical (QM) innovative approach. The quantum-refinement crystallographic method (crystallographic refinement enhanced with quantum mechanical calculation) was adapted to treat the [AuL]/G-quadruplex structure, where each gold complex in the binding site was found spread over four equally occupied positions. The four positions were first determined by docking restrained to the crystallographically determined metal ions' coordinates. Then, the quantum refinement method was used to resolve the poorly defined density around the ligands and improve the crystallographic determination, revealing that the binding preferences of this metallodrug toward Tel24 G-quadruplex arise from a combined effect of pyrimidine stacking, metal–guanine interactions and charge–charge neutralizing action of the π-acid triazine. The occurrence of interaction in solution with the Tel24 G-quadruplex DNA was further proved through DNA melting experiments, which showed a slight destabilisation of the quadruplex upon adduct formation.

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author
; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
DNA G-quadruplex, Gold complexes, Melting experiments, QM/MM, Quantum refinement, X-ray diffraction
in
International Journal of Biological Macromolecules
volume
211
pages
8 pages
publisher
Elsevier
external identifiers
  • scopus:85130779349
  • pmid:35561865
ISSN
0141-8130
DOI
10.1016/j.ijbiomac.2022.05.033
language
English
LU publication?
yes
additional info
Publisher Copyright: © 2022
id
4242dcf0-edeb-4563-ae39-e36398e1e254
date added to LUP
2022-08-19 13:49:17
date last changed
2024-06-13 10:14:20
@article{4242dcf0-edeb-4563-ae39-e36398e1e254,
  abstract     = {{<p>The crystal structure of the human telomeric DNA Tel24 G-quadruplex (Tel24 = TAG<sub>3</sub>(T<sub>2</sub>AG<sub>3</sub>)<sub>3</sub>T) in complex with the novel [AuL] species (with L = 2,4,6-tris(2-pyrimidyl)-1,3,5-triazine - TPymT-α) was solved by a novel joint molecular mechanical (MM)/quantum mechanical (QM) innovative approach. The quantum-refinement crystallographic method (crystallographic refinement enhanced with quantum mechanical calculation) was adapted to treat the [AuL]/G-quadruplex structure, where each gold complex in the binding site was found spread over four equally occupied positions. The four positions were first determined by docking restrained to the crystallographically determined metal ions' coordinates. Then, the quantum refinement method was used to resolve the poorly defined density around the ligands and improve the crystallographic determination, revealing that the binding preferences of this metallodrug toward Tel24 G-quadruplex arise from a combined effect of pyrimidine stacking, metal–guanine interactions and charge–charge neutralizing action of the π-acid triazine. The occurrence of interaction in solution with the Tel24 G-quadruplex DNA was further proved through DNA melting experiments, which showed a slight destabilisation of the quadruplex upon adduct formation.</p>}},
  author       = {{Cirri, Damiano and Bazzicalupi, Carla and Ryde, Ulf and Bergmann, Justin and Binacchi, Francesca and Nocentini, Alessio and Pratesi, Alessandro and Gratteri, Paola and Messori, Luigi}},
  issn         = {{0141-8130}},
  keywords     = {{DNA G-quadruplex; Gold complexes; Melting experiments; QM/MM; Quantum refinement; X-ray diffraction}},
  language     = {{eng}},
  month        = {{06}},
  pages        = {{506--513}},
  publisher    = {{Elsevier}},
  series       = {{International Journal of Biological Macromolecules}},
  title        = {{Computationally enhanced X-ray diffraction analysis of a gold(III) complex interacting with the human telomeric DNA G-quadruplex. Unravelling non-unique ligand positioning}},
  url          = {{https://lup.lub.lu.se/search/files/135489046/289_g5.pdf}},
  doi          = {{10.1016/j.ijbiomac.2022.05.033}},
  volume       = {{211}},
  year         = {{2022}},
}