A

Fig. 20. Circular dichroism (CD) spectra of sonicated calf thymus DNA in the presence of spermine in a buffer containing 10 mMsodium cacodylate, 0.5 mM EDTA, pH 7.4. Concentrations of spermine are as follows. (A) 0 (o), 0.015 (•), 0.03 (A), 0.05 (▲), and 0.10 (□) mM; (B) 25 (•), 75 (A), 90 (O), 100 (▲), 110 (♦), 125 (□), and 200 (n) mM. Because the solutions were not centrifuged, (B) shows the CD spectra of either aggregated DNA (•A) or resolubilized DNA (▲,♦,□,■). (Reprinted with permission from ref. 62. © 1999 American Chemical Society.)

Wavelength, nm

Fig. 20. Circular dichroism (CD) spectra of sonicated calf thymus DNA in the presence of spermine in a buffer containing 10 mMsodium cacodylate, 0.5 mM EDTA, pH 7.4. Concentrations of spermine are as follows. (A) 0 (o), 0.015 (•), 0.03 (A), 0.05 (▲), and 0.10 (□) mM; (B) 25 (•), 75 (A), 90 (O), 100 (▲), 110 (♦), 125 (□), and 200 (n) mM. Because the solutions were not centrifuged, (B) shows the CD spectra of either aggregated DNA (•A) or resolubilized DNA (▲,♦,□,■). (Reprinted with permission from ref. 62. © 1999 American Chemical Society.)

nature (53). However, other studies show that polyamine-DNA binding cannot be solely explained by the electrolytic theory and that structural specificities have to be considered to explain the true nature of polyamine-DNA binding (13).

The nonspecific electrostatic interaction theory of polyamine-DNA binding is supported by the polyelectrolyte and counterion condensation theories developed by Manning (65). According to these, the positively charged polyamines are structureless point charges that form an ionic cloud near the DNA surface from nonspecific electrostatic interactions with the negative phosphate groups of DNA. Site-specific interactions between polyamines and DNA are not considered in these models. This line of thought has been given credence by results from earlier solution studies that used equilibrium dialysis, nuclear magnetic resonance measurements on 23Na, 14N, and 1H nuclei, and calorimetric methods to study polyamine-DNA binding (13,66). However, evidence has been accumulating that suggest that the sequence and structure of DNA plays a significant role in determining polyamine-DNA binding. Site-specific interaction of polyamines with DNA is exemplified by preferential binding of polyamines with A-DNA and Z-DNA.

Experimental and theoretical methods have been used to determine the binding positions of polyamines on DNA. Most of these studies have focused on spermine, as it is often used to crystallize DNA from solution. Different and often contradictory ideas concerning the binding sites of spermine and other polyamines to DNA have been proposed. Energy minimization calculations using the (dG-dC)5/(dG-dC)5 model suggest the folding of the major groove of DNA around spermine with the widening of the minor groove and compaction of the intrastrand phosphate distances (33). Recent molecular modeling studies using a B-DNA model indicate that spermine binding is highly mobile with binding sites across major and minor grooves and around the phosphates, and is capable of forming bridges between different helices (32). Rapid diffusion of spermine along the DNA duplex with specific tight-binding sites or delocalized binding with no discrete sites has been suggested. Infrared studies agree with the modeling studies, demonstrating that there could be interstrand attachment at both the major and minor grooves, although the major groove is the preferred binding site of spermine (67). Raman spectroscopic studies by different investigators have indicated base-specific, as well as electrostatic interactions, independent of base composition (68,69). Thus, the binding positions of spermine and other polyamines appears to be unresolved and it is possible that the extent of spermine binding and its exchange with other cations and the hydration shell at any particular site depends on several parameters, including DNA sequence, geometry of grooves, and the nature of other cations and anions in the medium. The requirement of polyamines in the function of normal cells and their increased biosynthesis in diseases, such as cancer, has led to the development of synthetic polyamine analogs (70). Therefore, it is important to know how natural polyamines and synthetic analogs interact with nucleic acids.

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