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Three α-dicarbonyl compounds, methylglyoxal (MGO), diacetyl (DA) and glyoxal (GO) were common highly reactive glycosylation intermediates that can cause damage to biological macromolecules (e. g. DNA) in the body. The interaction properties of MGO, DA and GO with calf thymus DNA (ctDNA) were determined by multispectral methods combined with computer simulation techniques. Analysis of UV spectra indicated that MGO, DA and GO binding to ctDNA spontaneously were mainly driven by van der Waals forces and hydrogen bonding, and the energy distribution in molecular dynamics simulations supported this conclusion. The binding constants of MGO, DA and GO with ctDNA at 25 ℃ were close to those of classical groove-binders, with corresponding values of 2.99×10³, 1.96×10³ and 1. 05×10³ L·mol-1, respectively. NaCl, single and double-stranded DNA, thermal denaturation, viscosity and CD spectroscopy experiments demonstrated that MGO, DA and GO were all bound to ctDNA via groove binding. Molecular docking visualization showed that MGO, DA and GO were bound in the AT-rich minor groove region of DNA, with DT7 and DA18 being the active sites of binding. Molecular dynamics simulations of the MGO-ctDNA complex had higher root mean square deviation, radius of gyration, and root mean square fluctuation values than free DNA, indicating that the binding of MGO loosened and tended to destabilise parts of the DNA structure. Gel electrophoresis experiments showed that MGO, DA and GO could damage plasmid DNA in the presence of lysine and Cu2+, and MGO and GO even completely disrupted the superhelical morphology of DNA. [ABSTRACT FROM AUTHOR]