Galyuk Elena N, Fridman Alexander S, Vorob'ev Vladimir I, Haroutiunian Samvel G, Sargsyan Shushanik A, Hauruk Maryna M, Lando Dmitri Y
Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, 5/2, Kuprevich St., 220141, Minsk, Belarus.
J Biomol Struct Dyn. 2008 Feb;25(4):407-17. doi: 10.1080/07391102.2008.10507189.
Binding of the antitumor compound cisplatin to DNA locally distorts the double helix. These distortions correlate with a decrease in DNA melting temperature (Tm). However, the influence of cisplatin on DNA stability is more complex because it decreases the DNA charge density. In this way, cisplatin increases the melting temperature and partially compensates for the destabilizing influence of structural distortions. The stabilization is stronger at low Na+ ion concentration. Due to this compensation, the total decrease in the DNA melting temperature after cisplatin binding is much lower than the decrease caused by the distortions themselves, especially at low [Na+]. It is shown in this study that, besides Na+ concentration, pH also strongly influences the value of a change in the melting temperature caused by cisplatin. In alkaline medium (pH=10.5-10.8), a fall in the melting temperature caused by platination is enhanced several times with respect to neutral medium. Such a stronger drop in Tm is explained by a decrease in pK values of base pairs caused by lowering the charge density under platination that facilitates proton release. At neutral pH, the proton release is low for both control and platinated DNA and does not influence the melting behavior. Therefore, lowering in the charge density under platination, besides stabilization, gives additional destabilization just in alkaline medium. Destabilization caused by structural distortions due to this pH induced compensation of stabilizing effect is more pronounced. In the presence of carbonate ion, destabilization caused by high pH value is strengthened. As a decrease in DNA charge density, interstrand crosslinking caused by cisplatin also increases the DNA stability due to loss in the entropy of the melted state. However, computer modeling of DNA stability demonstrates that interstrand crosslinks formed by cisplatin do not stabilize long DNA. It is shown that the increase in Tm caused by interstrand crosslinking itself is compensated for by a local destabilization of the double helix at the sites of location of interstrand crosslinks formed by cisplatin.
抗肿瘤化合物顺铂与DNA的结合会使双螺旋局部扭曲。这些扭曲与DNA解链温度（Tm）的降低相关。然而，顺铂对DNA稳定性的影响更为复杂，因为它会降低DNA电荷密度。通过这种方式，顺铂提高了解链温度，并部分补偿了结构扭曲的去稳定作用。在低Na⁺离子浓度下，这种稳定作用更强。由于这种补偿作用，顺铂结合后DNA解链温度的总降低幅度远低于由扭曲本身引起的降低幅度，尤其是在低[Na⁺]时。本研究表明，除了Na⁺浓度外，pH值也强烈影响顺铂引起的解链温度变化值。在碱性介质（pH = 10.5 - 10.8）中，相对于中性介质，铂化引起的解链温度下降会增强数倍。这种Tm的更强下降是由于铂化作用下电荷密度降低导致碱基对的pK值下降，从而促进了质子释放。在中性pH值下，对照DNA和铂化DNA的质子释放都很低，且不影响解链行为。因此，铂化作用下电荷密度的降低，除了产生稳定作用外，仅在碱性介质中会产生额外的去稳定作用。由于这种pH诱导的稳定作用补偿导致的结构扭曲引起的去稳定作用更为明显。在碳酸根离子存在的情况下，高pH值引起的去稳定作用会增强。由于DNA电荷密度的降低，顺铂引起的链间交联也会由于熔融态熵的损失而增加DNA稳定性。然而，DNA稳定性的计算机模拟表明，顺铂形成的链间交联并不能稳定长链DNA。结果表明，链间交联本身引起的Tm升高会被顺铂形成的链间交联位置处双螺旋的局部去稳定作用所补偿。
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