Interações não covalentes entre SI-PPCs e biomoléculas: um estudo por simulações de dinâmica molecular

Abstract

Several studies with inert platinum (II) polynuclear complexes for substitution (SI-PPC) have been carried out in recent years due to the new DNA binding modes 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 changes in the major and minor DNA grooves. These compounds have also shown a high capacity to prevent the process of metastasis through interaction with other biomolecules that contain sulfate groups, such as glycosaminoglycans, stabilizing such groups and inhibiting the activity of enzymes that are related to the angiogenesis process and, consequently, the metastasis process. In this work, we use molecular dynamics (MD) simulations to study the formation of these cyclic structures between different SI-PPCs and biomolecules. The results showed the influence of the complex on the number of phosphate clamps and forks formed. Based on the conformational characterization of the DNA fragments, we show that the SI-PPCs studied here preferentially interact in the minor groove, except for two of them, monoplatinNC and AH44. The phosphates of the cytosine-guanine (C-G) pairs are the main sites for these noncovalent interactions. On the other hand, this work presents several analyzes of the non-covalent interactions formed between a heparin molecule (code PDB: 1HPN) and SI-PPCs obtained through molecular dynamics simulations. The results of the analysis of atomic positions showed that the diplatinNC and AH44 complexes, both complexes with 6+ charge, were the most rigid. On the other hand, an atomic fluctuation analysis showed that there is a reduction in the atomic fluctuation of atoms in the central region of the heparin molecule, as well as the analysis of the solvent accessible surface area (SASA) indicates a reduction in the accessible area of heparin by the solvent when interacting with SI-PPCs. The assessment of hydrogen bonds data confirms the formation of non-covalent bonds, which may suggest a decrease in the action of 1HPN preventing the action of enzymes on this substrate. As far as we know, this work is the first related to SI-PPCs that brings DM simulations and a complete analysis of non-covalent interactions with different biomolecules.