G force platinum key
As far as model types 2 and 6 are concerned, the IE is consistently defined by eq 2 (2)where E B1B2 is the energy of the dimer formed by the two bases. For the sake of clarity, hereafter, we decided to light notation by specifying in all cases E PtPPH. As shown in Figure 1, model type 1 accounts for the raw ligand PPH instead of the whole PtPPH so that in this case, the E PtPPH term corresponds to the energy of the ligand. The interaction energy (IE) for two-body systems, for example, model types 1, 4, and 5, is defined through the regular eq 1 (1)where E cluster is the total energy for the clusters, E PtPPH is the energy of the isolated PtPPH drug, and E B1 represents the energy of the single DNA base. All calculations were carried out with the Gaussian16 program. (72−75) To avoid unrealistic conformations, partial optimization was performed in three steps: first, the geometry was left to change without constraints then, in a second stage, the positions of the all skeleton atoms (phosphate and deoxyribose) were frozen in the third stage, the QM part was isolated, and with the optimized DFT level of theory described above, the coordinates of the four carbon atoms of the skeleton linked to the bases were frozen. (71) This QM/QM′ regime has been successfully used in the related biological system. The low layer (QM′) was modeled with the semiempirical PM6 method. (69,70) The high layer (QM) included the intercalated platinum complexes, and two adjacent base pairs (four bases) were treated with the DFT level of theory described in the previous section. A hybrid QM/QM′ scheme was used in these models as implemented in the ONIOM approach. The more complete type 3 and 7 models are characterized by large electronic and geometrical degrees of freedom. However, this study has been exclusively focused on the reaction of the aqua-activated complex of PtPPH when analyzing the interaction with nucleobases so that it remains unknown the reactivity of the parent chloro complex. have recently used density functional theory (DFT) calculations and classical molecular dynamics simulations to assess the hydrolysis, interaction with guanine (G), reactivity with N-acetyl methionine, and intercalation to DNA. In this framework, Dabbish (39,44) et al. Although such a computational approach provides first clues about the intercalation phenomena, more refined models must be implemented if biological conclusions are looked for. In the same work, a preliminary molecular docking of cis- and trans-PtPPH was performed. It is remarkable that the mechanism is largely sensitive to the stereochemistry at the metal center as only the cis-isomer has the proper conformation to produce irreversible DNA elongation upon covalent bond formation.
![g force platinum key g force platinum key](https://gamefabrique.com/storage/screenshots/genesis/burning-force-13.png)
The latter results suggested that the mechanism of binding involves a fast intercalation step which leads producing a stretching of the DNA, followed by a second slower reaction which is assigned to the covalent bond formation with the N7 atom of a purine base. Recently, the DNA–PtPPH interaction was revised by Lippard and co-workers (43) on the basis of the analysis of the time-dependent extensions of single λ-DNA molecules treated with the cis- and trans-isomers of PtPPH. In a recent contribution aimed at replicating the experimental conditions and the mechanisms of reactions between PtPPH and DNA bases, (38) we highlighted the possibility of formation of π–π interactions prior to the formation of the final covalent adduct. The impact of the DNA sequence and the lateral backbone was also discussed to provide a more complete picture of the forces that anchor the drug into the double helix. The permanent damage to DNA is consequently driven by that latter bond to DNA but with a simultaneous π–π intercalation of the phenanthridine into nucleobases.
![g force platinum key g force platinum key](https://www.nikktech.com/main/images/pics/reviews/corsair/k95_rgb_platinum_xt/corsair_k95_rgb_platinum_xt_review_10.jpg)
The performed simulations show that the cascade of reactions is articulated in three well-defined stages: (i) an early and fast intercalation of the complex between the DNA bases, (ii) a subsequent hydrolysis reaction that leads to the aqua-activated form, and (iii) a final formation of the covalent bond between PtPPH and DNA at a guanine site. Ab initio quantum mechanical (QM) methods, hybrid QM/QM′ schemes, and independent gradient model approaches are implemented in an unbiased protocol. Aiming to capture the mechanism of action of PtPPH, the present contribution used theoretical tools to systematically assess the sequence of all possible mechanisms on drug activation and reactivity, for example, hydrolysis, intercalation, and covalent damage to DNA. Although the aqua-activated drug has been assumed to be the precursor for DNA damage, it is still under debate whether the way in which that metallodrug attacks to DNA is dominated by a direct binding to a guanine base or rather by an intercalated intermediate product. Phenanthriplatin (PtPPH) is a monovalent platinum(II)-based complex with a large cytotoxicity against cancer cells.