Abstract
The anticancer activity of cisplatin arises from its ability to bind covalently to DNA, forming primarily intrastrand cross-links to adjacent purine residues; the most common adducts involve d(GpG) (65%) and d(ApG) (25%) intrastrand cross-links. The incorporation of these platinum adducts in a B-DNA helix induces local distortions, causing bending and unwinding of the DNA. In this work, we used temperature-dependent UV spectroscopy to investigate the unfolding thermodynamics, and associated ionic effects, of two sets of DNA decamer duplexes containing either cis-[Pt(NH3)2{d(GpG}] or cis-[Pt(NH3)2 {d(ApG}] cross-links, and their corresponding unmodified duplexes. The platinated duplexes are less stable and unfold with lower TMs (and ΔG°s) in enthalpy-driven reactions, which indicates a loss of favorable base-pair stacking interactions. The folding thermodynamics and hydration effects for the first set of decamers containing the d(GpG) cross-link was investigated by a combination of titration calorimetry, density, and ultrasound techniques. The hydration parameters showed an uptake of structural water by the platinated duplex and a release of electrostricted water by the control duplex. Relative to the unmodified duplex, the folding of the platinated duplex at 20°C yielded a positive ΔΔG° term [and positive ΔΔH-Δ(TΔS) compensation] and a negative differential volume change. The opposite signs of the ΔΔG° and ΔΔV terms confirmed its uptake of structural water. Further, solvent-accessible surface areas calculations for a similar pair of dodecamer duplexes indicated that the modified duplex has a 503 æÅ2 higher polar and nonpolar surface area that is exposed to the solvent. Therefore, the incorporation of a platinum adduct in duplex DNA disrupts favorable base-pair stacking interactions, yielding a greater exposure of aromatic bases to the solvent, which in turn immobilizes structural water. The overall results correlate nicely with the results reported in the available structural data of nuclear magnetic resonance solution studies.
Original language | English (US) |
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Pages (from-to) | 218-227 |
Number of pages | 10 |
Journal | Biopolymers |
Volume | 65 |
Issue number | 3 |
DOIs | |
State | Published - Nov 5 2002 |
Keywords
- Cisplatin
- Compressibility
- DNA
- DNA bending
- Heat
- Stability
- Structural hydration
- Thermodynamics
- Ultrasound velocity
- Volume
ASJC Scopus subject areas
- Biophysics
- Biochemistry
- Biomaterials
- Organic Chemistry