Mechanistic studies of electron transfer dissociation of natural and sugar-modified DNA

There is a dual interest in short nucleic acids in medical research: They present potential targets of, for instance, platinum-based anti-tumour drugs or function as active agents themselves in antisense therapy. This potential motivates the development of reliable analytical techniques like tandem mass spectrometry for the structure elucidation of natural and modified nucleic acid. Most published studies on tandem mass spectrometric characterisation and sequencing of nucleic acids rely on collisional activation. While collision-induced dissociation (CID) gives rise to a series of sequence-specific fragment ions, unspecific loss of water and nucleobases is observed as well. The contribution of these alternative channels is reduced when radical activation methods, such as electron transfer dissociation (ETD), are applied. However, the fragmentation of the oligonucleotide radical ions in the gas-phase is not yet fully understood. Our work on the ETD fragmentation of DNA and sugar-modified analogues aims to shed light on the dissociation mechanism. ETD experiments in the positive ion mode demonstrate that the preferred cleavage site depends on the nucleobase sequence. Moreover, the efficiency of backbone cleavage is higher in sugar-modified analogues, in which the distance between adjacent nucleobases is almost 1.5 times higher than in natural DNA. This difference indicates that nucleobase stacking may stabilize the radical ion and reduce the yield of backbone cleavage