Unrestrained 5 ns molecular dynamics simulation of a cisplatin-DNA 1,2-GG adduct provides a rationale for the NMR features and reveals increased conformational flexibility at the platinum binding site.

A 5 ns unrestrained molecular dynamics (MD) simulation of the DNA duplex d(GCCG*G*ATCGC)-d(GCGATCCGGC), bearing a cis-Pt(NH(3))(2)(2+) unit crosslinking the two G* guanine bases, is reported. The MD trajectory was a posteriori correlated with NMR data determined for the same adduct, and it is shown that interproton distances and the characteristic chemical shifts are accounted for by the simulation. The simulation and its confrontation with the NMR data have confirmed the finding derived early from static models that the cytosine complementary to the 5' G*, C17, is mobile with respect to its adjacent bases. However, in contrast to our previous description of this mobility, which included rupture of the Watson-Crick hydrogen bonds and formation of non-Watson-Crick hydrogen bonds, the MD simulation indicated that the G*4-C17 pair moves continuously along a trajectory roughly perpendicular to the local helix axis, with retention of all three Watson-Crick hydrogen bonds. The simulation indicated the reversible formation of a hydrogen bond between the 5' oriented NH(3) ligand of platinum and the C3pG*4 phosphate group, in accord with our former prediction. Furthermore, the simulation has disclosed previously undetected BI <=> BII transitions at the G*5pA6 and A6pT7 steps, connected to formation/rupture of a hydrogen bond between the 3' oriented NH(3) ligand of platinum and the N7 atom of A6. All these conformational equilibria affect the form of the minor groove and increase the conformational flexibility at the platination site, and are thus likely to facilitate recognition by cellular proteins. Copyright 2001 Academic Press.