Differences in conformational dynamics of [Pt3(HPTAB)]6+-DNA adducts with various cross-linking modes

Abstract

We present here molecular dynamics simulations and DNA conformational dynamics for a series of trinuclear platinum [Pt(3)(HPTAB)](6+)-DNA adducts [HPTAB = N,N,N',N',N'',N''-hexakis (2-pyridyl-methyl)-1,3,5-tris(aminomethyl) benzene], including three types of bifunctional crosslinks and four types of trifunctional crosslinks. Our simulation results reveal that binding of the trinuclear platinum compound to a DNA duplex induces the duplex unwinding in the vicinity of the platination sites, and causes the DNA to bend toward the major groove. As a consequence, this produces a DNA molecule whose minor groove is more widened and shallow compared to that of an undamaged bare-DNA molecule. Notably, for trifunctional crosslinks, we have observed extensive DNA conformational distortions, which is rarely seen for normal platinum-DNA adducts. Our findings, in this study, thus provide further support for the idea that platinum compounds with trifunctional intra-strand or long-range-inter-strand cross-linking modes can generate larger DNA conformational distortions than other types of cross-linking modes.

Chart 1.

X-ray structure of the trinuclear platinum compound (39).

Chart 2.

The 18-mer DNA sequence and seven Pt–DNA cross-linking modes studied in this work along with their assigned names (39). Three types of bifunctional crosslinks: I: 4,7-DNA; II: 26,28-DNA; III: 7,28-DNA Four types of trifunctional crosslinks: IV: 3,4,7-DNA; V: 26,28,29-DNA; VI: 4,7,28-DNA; VII: 7,28,26-DNA.

Figure 1.

The RMSD values of all backbone atoms for (a) the simulations of B-DNA and bifunctional crosslinks and (b) the simulations of trifunctional crosslinks with respect to the corresponding starting structures.

Figure 2.

The average centroid structures of seven adducts (the double-strand DNA backbones (green) with an arrow from 5′- to 3′-side in ribbon, and the studied platinum compounds in stick (pink)) along with an undamaged B-DNA (light yellow). (a) 4,7-DNA, (b) 26,28-DNA, (c) 7,28-DNA, (d) 3,4,7-DNA, (e) 26,28,29-DNA, (f) 4,7,28-DNA and (g) 7,28,26-DNA.

Figure 3.

Hydrogen bond occupancies of base pairs along with base-pair steps for each adduct: (a) for 4,7-DNA (square), 26,28-DNA (down-triangle), 7,28-DNA (circle); (b) 3,4,7-DNA (square), 26,28,29-DNA (circle), 4,7,28-DNA (up-triangle) and 7,28,26-DNA (down-triangle).

Figure 4.

Hydrogen bonds between platinum ligands and DNA: the bases in DNA and the platinum compound in tube, carbon atoms in gray, nitrogen atoms in blue, oxygen atoms in red and hydrogen atoms in white; (a) 4,7-DNA, (b) 26,28-DNA, (c) 3,4,7-DNA and (d) 4,7,28-DNA.

Figure 5.

Selected frequency distributions of the representative DNA duplex helical parameters for the central binding base pairs for the bifunctional crosslinks.

Figure 6.

Selected frequency distributions of the representative DNA duplex helical parameters for the central binding base pairs for the trifunctional crosslinks.

Figure 7.

Minor groove widths and depths for the time-averaged structures of the DNA conformations in the four types of the trifunctional crosslinks: (a) and (b): B-DNA (red line with diamond), 3,4,7-DNA (black line with square), 26,28,29-DNA (magenta line with circle), 4,7,28-DNA (blue line with up-triangle), and 7,28,26-DNA (green line with circle); (c): the minor groove parameters of DNA in the 26,28,29-DNA adduct (magenta line with circle for width and light-orange line with diamond for depth).

Figure 8.

Conformation details of DNA base pairs in the 26,28,29-DNA adduct along with the corresponding undamaged B-DNA base pairs: double-strand DNA backbone with light blue and the undamaged B-DNA with light yellow. (a) Front view of DNA backbone for 8–11 bp; (b) side view of DNA backbone.