Molecular Mechanics Modeling of Oligonucleotide Adducts of the Antitumor Drug zy cis-Diamminedichloroplatinum( 11) zy J I R i KOZELKA, SHARON ARCHER, GREGORY A. PETSKO, STEPHEN J. LIPPARD, Department zyxw of Chemistry, Massachusetts zy Institute of Techmlogy, C a m b e e , Massachusetts zyx 02139; and GARY J. QUIGLEY, Department of Biology, Massachusetts Institute of Technology, Camblzdge, Massachusetts 02139 Synopsis In order to assess the geometric changes caused when the antitumor drug cis-diammine- dichloroplatinum(I1) (cis-DDP) binds to DNA, molecular mechanics calculations were performed on two double-stranded and two single-stranded oligonucleotides and their adducts with cis-( Pt(NH,),}'+. For the platinated duplexes, three model structures have been derived, one involving only local disruption of base pairing with retention of the helix directionality, and two models showing pronounced kinking of the double helix. One of the kinked models is stabilized by bridging sodium ions. The other kinked duplex model shows retention of all Watson-Crick base pairing, including that of the coordinated guanines. All models exhibit hydrogen bonds connecting one ammine ligand of platinum with one or two phosphate groups located a t the 5' side of the platinated strand. INTRODUCTION It is now widely accepted that the antitumor drug cis-diamminedichloro- platinum(I1) (cis-DDP) binds predominantly to d(GpG) sites of DNA (for a review, see Ref. 1). 'H- and 31P-nmr techniques have been used to explore structural changes caused by the binding of cis-DDP to oligon~cleotides.~-~ One possible interpretation of the nmr results for platinated duplexes pos- tulates the formation of a kink on the B-DNA double helix upon binding of platin~m.~ This hypothesis is attractive since kinks in the duplex could account for the shortening and unwinding of superhelical DNA observed following platination.lO.l' Definitive evidence for a kinked structure remains elusive, however. It is also uncertain to what extent the binding of cis-DDP affects base pairing. Studies of the 'H-nmr signals assigned to the imino protons of the coordinated guanines revealed that, below 28"C, these protons are still involved in some type of hydrogen bonding. At higher temperatures, however, the imino hydrogen bonds of the coordinated guanines are the first to be di~rupted.~,~ Because a profound nmr investigation of the amino protons is still lacking, a more detailed picture of the effects of cis-DDP on base pairing has not yet been derived. Biopolymers, Vol. 26, 1245-1271 zyxwvu (1987) zyxwvu 0 1987 John Wiley & Sons, Inc. CCC OOO6-3525/87/081245-27$04.00