Nucleotide and Metal-DNA Interactions

In the process, force-field parameters for theplatinum(II)-nucleotide interactions were developed. In two more recent studies the force fields for purine-platinum(II) complexes have been reassessed and the influence of repulsions involving the metal ion investigated [143,144]. The van der Waals radii derived for the platinum(II) ion varied from 1.7 to 2.44 A A promising approach involving the use of ab-initio calculations to determine force constants has been appUed to the interaction between platinum(II) and adenine [521]. 

Numerous studies have been conducted on the interaction of the highly effective anticancer drug cisplatin, cis-[PtCl2(NH3)2], with DNA. The majority of these studies have concentrated on the adduct formed between the platinum(II) ion and two adjacent guanine bases (G) on one strand of DNA this is the adduct formed most frequently in the interaction between platinum and DNA For instance, such adducts 

The observation that cisplatin forms adducts with the GpG and ApG (G = guanine, A = adenine, p = phosphate) sequences of DNA, but not with the GpA sequence, has also been probed by molecular mechanics [198,199], In this case it was found that the nature of the interactions of one of the ammine ligands depended on the base on the 3 side (the second in the sequence). When this base is guanine, the interaction is a strong hydrogen bond, but when it is adenine the interaction is a repulsive interaction between the same ammine ligand and the exocydic -NH 2 group of the adenine. This is consistent with formation of the adducts with GpG and ApG and non-formation of the adduct with GpA. 

Models of adducts that link one strand of DNA to the other (interstrand) have also been produced [199, 527]. These too, reveal hydrogen-bonding interactions consistent with established structure-activity relationships. The models have been used to aid in the design of new platinum(II) complexes that should form the interstrand adducts in preference to intrastrand adducts [528]. 

Stereo- and enantio-selectivity arising from steric interactions between DNA and bulky platinum(II) complexes have been investigated by molecular mechanics. Good correlations between the extent of binding and steric interactions were obtained for the R and S enantiomers of [PtGl2(ahaz)[ (ahaz = 3-aminohexahydroazepine) [529]. 

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Molecular mechanics and dynamics studies of metal-nucleotide and metal-DNA interactions to date have been limited almost exclusively to modeling the interactions involving platinum-based anticancer drugs. As with metal-amino-acid complexes, there have been surprisingly few molecular mechanics studies of simple metal-nucleotide complexes that provide a means of deriving reliable force field parameters. A study of bis(purine)diamine-platinum(II) complexes successfully reproduced the structures of such complexes and demonstrated how steric factors influenced the barriers to rotation about the Pt(II)-N(purine) coordinate bonds and interconversion of the head-to-head (HTH) to head-to-tail (HTT) isomers (Fig. 12.4)[2011. In the process, force field parameters for the Pt(II)/nucleotide interactions were developed. A promising new approach involving the use of ab-initio calculations to calculate force constants has been applied to the interaction between Pt(II) and adenine[202]. 

Electrostatically-controlled pre-association interactions have an important effect on rates for [Pd(dien)Cl]+ reacting with thione-containing nucleosides, nucleotides and oligonucleotides, as is often the case for reactions between metal complexes and this type of biological ligand. Interaction between the charged complex and the polyanionic oligonucleotide surface leads to an increase in both enthalpy and entropy of activation in the DNA or model environment (252). 

There has been considerable interest in recent years in the formation of condensed films of purine and pyrimidine bases at the solid-liquid interface. It is well recognised that non-covalent affinities between base pairs play a prevalent role in determining nucleic acid conformation and functionality. Likewise, there has been interest in the role of substrate and non-covalent intermolecular interactions in the configuration of ordered monolayers of purine and pyrimidine bases. There is also more general interest in the interaction of bases with metal surfaces and metal complexes. In the latter case it is noted that the biological role of nucleic acids and certain nucleotides are dependent on metal ions, particularly Mg, Ca, Zn, Mn, Cu and Ni. " Also certain metal complexes, notably of platinum, have the anti-tumour activity, which is linked to their ability to bind to bases on DNA. On a different note, the possibility that purine-pyrimidine arrays assembled on naturally occurring mineral surfaces might act as possible templates for biomolecular assembly has been discussed by Sowerby et al. 

Fritzsche, H., Arnold, K., and Krusche, R. (1974). Stud. Biophys. 45, 131. Interactions of DNA and Metal Ions. Carbon-13 nmr Study of Some Nucleosides and Nucleotides Adding Copper(Il) and Manganese(Il) Ions. Imoto, T., Akasaka, K., and Hatano, H. (1975). Chem. Phys. Lett. 32, 86. Rotational Correlation Times of Adenosine 5 -Monophosphate in Solution as Deduced From Proton and Carbon-13 Spin-Lattice Relaxation Times. 

Building towards models relevant for polymeric DNA and RNA, nucleotides contain a phosphate attached at the 5 or 3 position. The 5 -nucleotides are most commonly studied, for which the phosphate has a pAa 6 for the first protonation step. Unless otherwise noted, throughout this chapter nucleotide will refer to the 5 -phosphate linkage. In nucleotides, metal-phosphate coordination competes with metal-base interactions. Chelate complexes with both phosphate and base coordination can occur when sterically allowed. Thus, transition metal complexes with purine monophosphates tend to exhibit metal coordination to the base N7 position, with apparent hydrogen bonding of coordinated waters to the phosphate. By contrast, more ionic Mg" binds preferentially to the phosphate groups in nucleotide monophosphates. In di- and tri-phosphate complexes such as metal-ATP compounds, the proximity of multiple phosphates generally favors polyphosphate chelate complexes with metal ions. 

Abstract This review summarizes computational studies devoted to interactions of metal cations with nucleobases, nucleotides, and short oligonucleotides considered as DNA/RNA models. Since this topic is complex, basically only the results obtained using ab initio and DFT methods are discussed. Part 1 focuses mainly on the interactions of the isolated bases with metal cations in bare, hydrated, and ligated forms. First, interactions of bare cations with nucleobases in gas phase approach are mentioned. Later, solvation effects using polarizable continuum models are analyzed and a comparison with explicitly hydrated ions is presented. In Part II, adducts of alkali metal, metal of alkaline earth, and zinc group metal cations with canonical base pairs are discussed. A separate section is devoted to platinum complexes related to anticancer treatment. Stacked bases and larger systems are discussed in last section. Here, semiempirical methods and molecular modeling are also discussed due to extensive size of studied complexes. 

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