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Conformational rearrangement of 1,2-d(GG) intrastrand cis-diammineplatinum crosslinked DNA is driven by counter-ion penetration within the minor groove of the modified site

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Abstract

The major structural aberrations of DNA induced by a cis-diammineplatinum (II) 1,2-d(GG) intrastrand cross-link (CPT) have been known for decades. To gain deeper insights into the structural dynamics of the sequence-dependent DNA distortions adjacent to the CPT adduct, we employed molecular modeling and molecular dynamics (MD) simulations. The structural dynamics of native (N-DNA) and cisPt 1,2-d(GG) crosslinked (CPT-DNA) in the form of symmetric 36 nt d(G2T15G*G*T15G2)●C2A15CCA15C2) oligonucleotide duplexes is compared. The selected sequence context enabled tracking of the origin of the DNA axis curvature at the YpR flexible points (N-DNA), the enhancement of axis bending, and further distortions due to steric/electrostatic perturbations arising from the CPT-crosslink. In addition to the known structural distortions of CPT-DNA: helix bend towards the major groove; local helix unwinding; high roll angle between cross-linked guanine bases; and adoption of A-form DNA on the 5′-side of the CPT-crosslink (TpG junction); our results show the existence of a singular irreversible and reproducible conformational rearrangement, not previously observed, resulting in two stable CPT-DNA1 and CPT-DNA2 conformers. The CPT-DNA2 conformation presents an enhanced DNA axis bend and a wider and shallower minor grove with increased solvent accessibility within the modified site. It is concluded that the polymorphous (unstable) DNA environment near the cisPt 1,2-d(GG) unit in synergy with specific dynamic events, such as prolonged minor groove retention of particular Na+ ions and water redistribution within the d(TG*G*T) site, together with the formation of extra and more stable H-bonds between Pt(NH3)2 amines and neighboring nucleotides, are cooperatively responsible for the initiation of the conformational rearrangement leading to the CPT-DNA2 conformer, which, surprisingly, closely resembles the HMGB1-bound CPT-DNA structure.

Superimposed averaged structures of normal (N-DNA, green) and cisplatin intrastrand cross-linked (CPT-DNA, orange). Global DNA axes: N-DNA (blue beads); CPT-DNA (red beads); PT (yellow sphere); crosslinked dGs viewed from the minor groove (bold)

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Acknowledgments

Supercomputer CPU time allocation at the National Supercomputing Center (NSC, Sofia, Bulgaria) and methodological support by its staff and Director (Prof. St. Markov) are gratefully acknowledged.

Funding

This work was supported by the National Science Fund at the Ministry of Education and Science, grant # B01/20–2012 and by a NSERC Discovery grant (DH).

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Authors and Affiliations

  1. Department of Nuclear Medicine & Radiobiology, Faculty of Medicine, Université de Sherbrooke, Sherbrooke, QC, J1H 5N4, Canada

    Tsvetan G. Gantchev & Darel J. Hunting

  2. “Roumen Tsanev” Institute of Molecular Biology, Bulgarian Academy of Sciences, 1113, Sofia, Bulgaria

    Tsvetan G. Gantchev

  3. Department of Atomic Physics, Faculty of Physics, Sofia University, 5 James Bourchier Blvd., 1164, Sofia, Bulgaria

    Peicho St. Petkov

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  1. Tsvetan G. Gantchev
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Correspondence to Tsvetan G. Gantchev.

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Gantchev, T.G., Petkov, P.S. & Hunting, D.J. Conformational rearrangement of 1,2-d(GG) intrastrand cis-diammineplatinum crosslinked DNA is driven by counter-ion penetration within the minor groove of the modified site. J Mol Model 23, 278 (2017). https://doi.org/10.1007/s00894-017-3445-2

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