Molecular dynamics simulation of non-covalent interactions between polynuclear platinum(II) complexes and DNA
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ORIGINAL PAPER
Molecular dynamics simulation of non‑covalent interactions between polynuclear platinum(II) complexes and DNA Nathália M. P. Rosa1 · Júlio A. F. Arvellos1 · Luiz Antônio S. Costa1 Received: 28 April 2020 / Accepted: 30 August 2020 © Society for Biological Inorganic Chemistry (SBIC) 2020
Abstract Several studies with substitution-inert polynuclear platinum(II) complexes (SI-PPC) have been carried out in recent years due to the form of DNA binding presented by these compounds. This form of bonding is achieved by molecular recognition through the formation of non-covalent structures, commonly called phosphate clamps and forks, which generate small extensions of the major and minor grooves. In this work, we use molecular dynamics simulations (MD) to study the formation of these cyclical structures between six different SI-PPCs and a double DNA dodecamer, here called 24_bp_DNA. The results showed the influence of the complex expressed on the number of phosphate clamps and forks formed. Based on the conformational characterization of the DNA fragment, we show that the studied SI-PPCs interact preferentially in the minor groove, causing groove spanning, except for two of them, Monoplatin and AH44. The phosphates of C–G pairs are the main sites for such non-covalent interactions. The Gibbs interaction energy of solvated species points out to AH78P, AH78H, and TriplatinNC as the most probable ones when coupled with DNA. As far as we know, this work is the very first one related to SI-PPCs which brings MD simulations and a complete analysis of the non-covalent interactions with a double DNA dodecamer. Keywords Phosphate clamps · Intermolecular interactions · TriplatinNC · Molecular dynamics · Force field parametrization · Major and minor groove
Introduction Platinum anticancer agents represent a class of drugs that are prominent in the treatment of this disease and are widely used. The highlight of this class is cisplatin, which has a cure rate above 95% in patients with testicular cancer. The success of cisplatin in the treatment of cancer is due to its ability to form covalent adducts with DNA and alter the structure. Upon entering the cell, this drug undergoes successive hydrolysis reactions to form activated aquo species as [Pt(NH3)2Cl(OH2)]+ and [Pt(NH3)2(OH2)2]2+ that will bind covalently to the DNA of different ways with N7 atoms Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00775-020-01817-9) contains supplementary material, which is available to authorized users. * Luiz Antônio S. Costa [email protected] 1
NEQC‑Núcleo de Estudos em Química Computacional, Departamento de Química, ICE, Universidade Federal de Juiz de Fora, Juiz de Fora, MG 36036‑900, Brazil
of the purine bases (G or A) [1, 2]. Two other platinumcontaining drugs are also approved worldwide for the treatment of cancer in humans, carboplatin, and oxaliplatin, in addition to three others that are approved for use in specific countries known as nedaplatin (Japan), lobapl
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