Melting of Crosslinked DNA: VI. Comparison of Influence of Interstrand Crosslinks and Other Chemical Modifications Formed by Antitumor Compounds on DNA Stability

• Published in: Journal of biomolecular structure & dynamics 2008-10, Vol.26 (2), p.175-185
• Main Authors: Fridman, Alexander S., Galyuk, Elena N., Vorob'ev, Vladimir I., Skvortsov, Alexei N., Lando, Dmitri Y.
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemistry; Cisplatin - chemistry; Cross-Linking Reagents - chemistry; DNA - chemistry; DNA - metabolism; Nucleic Acid Denaturation; Thermodynamics
• ISSN: 0739-1102; 1538-0254
• DOI: 10.1080/07391102.2008.10507233

A computer modeling of thermodynamic properties of a long DNA of N base pairs that includes ω interstrand crosslinks (ICLs), or ω chemical modifications involving one strand (monofunctional adducts, intrastrand crosslinks) has been carried out. It is supposed in our calculation that both types of chemical modifications change the free energy of the helix-coil transition at sites of their location by δF. The value δF>0 corresponds to stabilization, i.e. to the increase in melting temperature. It is also taken into account that ICLs form additional loops in melted regions and prohibit strand dissociation after full DNA melting. It is shown that the main effect of interstrand crosslinks on the stability of long DNA's is caused by the formation of additional loops in melted regions. This formation increases DNA melting temperature (T m ) much stronger than replacing co base pairs of AT type with GC. A prohibition of strand dissociation after crosslinking, which strongly elevates the melting temperature of oligonucleotide duplexes, does not influence melting behavior of long DNA's (N≥1000 bp). As was demonstrated earlier for the modifications involving one or the other strand, the dependence of the shift of melting temperature δT m on the relative number of modifications r = ω/(2N) is a linear function for any δF, and δT m (r) = 0 for the ideal modifications (δF=0). We have shown that δT m (r) is the same for periodical and random distribution if the absolute value of δF is less 2 kcal. The absolute value of δT m (r) at δF>2 kcal and δF