Melting of crosslinked DNA: VI. Comparison of influence of interstrand crosslinks and other chemical modifications formed by antitumor compounds on DNA stability.
A computer modeling of thermodynamic properties of a long DNA of N base pairs that includes omega interstrand crosslinks (ICLs), or omega 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 deltaF. The value deltaF>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 (Tm) much stronger than replacing omega 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>or=1000 bp). As was demonstrated earlier for the modifications involving one or the other strand, the dependence of the shift of melting temperature deltaTm on the relative number of modifications r=omega/(2N) is a linear function for any deltaF, and deltaTm(r) identical with 0 for the ideal modifications (deltaF=0). We have shown that deltaTm(r) is the same for periodical and random distribution if the absolute value of deltaF is less 2 kcal. The absolute value of deltaTm(r) at deltaF>2 kcal and deltaF<-2 kcal is higher for periodical distribution. For interstrand crosslinks, the character of the dependence deltaTm(r) is quite different. It is nonlinear, and the shape of the corresponding curve is strongly dependent on deltaF. For "ideal" interstrand crosslinks (deltaF=0), the function deltaTm(r) is not zero. It is monotone positive nonlinear, and its slope decreases with r. If r<0.004, then the entropy stabilizing effect of interstrand crosslinking itself exceeds the influence of a distortion of the double helix at sites of their location. The resulting deltaTm(r) is positive even in the case of the infinite destabilization at sites of the ICLs (deltaF-->-infinity). In general, stabilizing influence of interstrand crosslinks is almost fully compensated for by local structural distortions caused by them if 0<r<0.01 and -infinity<deltaF< approximately -5 kcal per mole of ICLs. The absolute value of deltaTm(r) in this case is approximately 10 times lower than for ideal ICLs as well as for local destabilization without crosslinking. Interstrand crosslinks formed by cisplatin do not change the melting temperature of long DNA's because of this compensation effect.
Fridman
Alexander S
AS
Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, 5/2, Kuprevich St., 220141, Minsk, Belarus.
Galyuk
Elena N
EN
Vorob'ev
Vladimir I
VI
Skvortsov
Alexei N
AN
Lando
Dmitri Y
DY
D000970:Antineoplastic Agents / Q000737:chemistry*; D002945:Cisplatin / Q000737:chemistry; D003432:Cross-Linking Reagents / Q000737:chemistry*; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D009691:Nucleic Acid Denaturation; D013816:Thermodynamics
D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D004247:DNA; D002945:Cisplatin