MOLECULAR MECHANICS ANALYSIS OF THE STEREOCHEMICAL FACTORS INFLUENCING MONOFUNCTIONAL AND BIFUNCTIONAL BINDING OF CIS-DIAMMINEDICHLOROPLATINUM(II) TO ADENINE AND GUANINE NUCLEOBASES IN THE SEQUENCES D(GPAPGPG).D(CPCPTPC) AND D(GPGPAPG).D(CPTPCPC) OF A-DNA AND B-DNA

Monofunctional and bifunctional binding of cis-diamminedichloroplatinum(II) (DDP) to the guanine and/or adenine bases of the sequences d(GpApGpG).d(CpCpTpC) and d(GpGpApG).d(CpTpCpC) of A- and B-DNA have been modeled by molecular mechanics. The stereochemical factors that influence the tendencies for sequence specific binding are described. Monofunctional binding of DDP produces significant changes in the conformational geometry of the DNA. In particular, the bases are rotated by up to 20-degrees, altering the distance from the Pt atom to potential binding sites on adjacent residues and making the distances to the 5'- and 3'-bases approximately equal. This is in contrast to the unequal distances predicted on the basis of idealized models of A- and B-DNA. Models for bifunctional adducts with ApG sequences are similar to those seen for bifunctional adducts with GpG sequences in that an NH3 ligand makes a hydrogen bond with O6 of the 3'-guanine. In contrast, models for bifunctional adducts with GpA sequences have a highly unfavorable contact between the equivalent NH3 ligand and the NH2 of the 3'-adenine. Five-coordinate transition-state models show that these interactions persist and are potentially important in determining the frequency of occurrence of the A*pG* and G*pA* adducts.