ORIGINAL PAPER 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 Tsvetan G. Gantchev 1,2 & Peicho St. Petkov 3 & Darel J. Hunting 1 Received: 25 August 2016 /Accepted: 25 August 2017 # Springer-Verlag GmbH Germany 2017 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 sym- metric 36 nt d(G 2 T 15 G*G*T 15 G 2 )●C 2 A 15 CCA 15 C 2 ) oligonu- cleotide 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 bend- ing, and further distortions due to steric/electrostatic perturba- tions 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 con- formers. 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 environ- ment 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(NH 3 ) 2 amines and neighbor- ing 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. Keywords DNA dynamic structure . Cisplatin . Intrastrand crosslink . Molecular modeling . Molecular dynamics . Conformational rearrangement, counter ion and water dynamics Introduction The anticancer activity of the cisplatin drug, cis-[PtCl 2 (NH 3 ) 2 ] results from the formation of several covalent DNA adducts, the most frequent of which is the 1,2-GpG intrastrand crosslink referred to here as (CPT-DNA). The presence of CPT adducts in DNA triggers several specific cellular re- sponses, including inhibition of replication, transcription and DNA repair, cell cycle arrest, and, potentially, cell death [1, 2]. CPT-DNA has been shown to interact with a number of cel- lular proteins, the most studied of which is the high-mobility group protein 1 (HMGB1), which is a non-sequence specific, non-histone, chromatin remodeler implicated in DNA damage repair [ 3–5]. CPT-DNA is a recognized substrate for Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00894-017-3445-2) contains supplementary material, which is available to authorized users. * Tsvetan G. Gantchev tsvetan.gantchev@usherbrooke.ca 1 Department of Nuclear Medicine & Radiobiology, Faculty of Medicine, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada 2 BRoumen Tsanev^ Institute of Molecular Biology, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria 3 Department of Atomic Physics, Faculty of Physics, Sofia University, 5 James Bourchier Blvd., 1164 Sofia, Bulgaria J Mol Model (2017) 23:278 DOI 10.1007/s00894-017-3445-2