Denaturation DNA Structure Induced By Cadmium-thymine Binding Specifically In Major Groove Of Sequence

The effect of.cadmium on human health has been drawing public concern.Expose to cadmium can cause acute and chronic lesions to tissues and organs.Moreover,a large amount of studies have reported that cadmium toxicity is related to cancer.However,the carcinogenic mechanism of cadmium is controversial.The underlying mechanism is conventionally attributed to the destruction of oxidative status in homeostasis by cadmium ioin(Cd2+),which indirectly destructs the cell components included DNA.Additionally,many studies reported that the destructed homeostasis further interfered the DNA repair systems,which caused the accumulation of DNA damage and increased the mutations.However,there is rare reports of direct DNA damage caused by cadmium.In this paper,applying molecular dynamics simulation(MD)and quantum mechanics simulation(QM).we studied the direct interaction of Cd2+ and dsDNA segment.We found that Cd2+ bound specifically to thymine in the major groove,which destructed the hydrogen bonds(HB)between adenine and thymine base pair and resulted in a mismatched structure of dsDNA.Besides,it was proved that this bonding state was stable at room temperature and irreversible.This structure subsequently caused the denaturation of dsDNA and created a single nucleotide polymorphism(SNP)on both the coding and noncoding regions of the genes.We presented a new binding state of cadmium ion directly bound to DNA.Moreover,this Cd-induced structure cannot break DNA strand.Therefore this kind of Cd2+-related mismatched structure is easily missed by laboratory detection.Our findings may be helpful for the facilitation of experimental detection of the ion’s binding sites.Additionally,it may also contribute an important step towards the understanding of the genotoxicity of cadmium.