An Investigation on the Fundamental Interaction between Abeta Peptides and the AT-Rich DNA

作者：Zhao Li Na; Zheng Jie; Chew Lock Yue^*; Mu Yuguang

来源：Journal of Physical Chemistry B, 2015, 119(26): 8247-8259.

DOI：10.1021/acs.jpcb.5b00957

DNA damage is ubiquitous in all mammalian cells with the occurrence of more than 60000 times per day per cell. In particular, DNA damage in neurons is found to accumulate with age and has been suggested to interfere with the synthesis of functional proteins. Moreover, recent studies have found through transgenic mice that human amyloid precursor protein causes an increase in DNA double-strand breaks (DSBs) with the effect of a prolongation in DNA repair. It is surmised that amyloid beta (A beta) exacerbates the DNA DSBs in neurons, possibly engendering neuronal dysfunction as a result. However, a good understanding on the holistic interaction mechanisms and the manner in which A beta intertwines with DNA damage is still in its infancy. In our study, we found that DNA with an AT-rich sequence has a very low binding affinity toward A beta by means of molecular dynamics simulation. While we have pursued a particular sequence of DNA in this study, other DNA sequences are expected to affect the interaction and binding affinity between DNA and A beta, and will be pursued in our further research. Nonetheless, we have uncovered favorable interaction between the positively charged side chain of A beta and the two ends of DNA. The latest experiment reveals that many of the double-stranded breaks in neurons can be fixed via DNA repair mechanisms but not in the case that A beta s are present. It is found that the increased numbers of DSBs prevail in active neurons. Here, on the basis of the favorable interaction between A beta and the two ends of DNA, we propose the possibility that A beta prevents DNA repair via binding directly to the break ends of the DNA, which further exacerbates DNA damage. Moreover, we have found that the base pair oxygen of the DNA has a greater preference to form hydrogen bonds than the backbone oxygen with A beta at the two ends. Thus, we postulate that A beta could serve to prevent the repair of AT-rich DNA, and it is unlikely to cause its breakage or affect its binding toward histone. Another important observation from our study is that AT-rich DNA has very little or no influence on A beta oligomerization. Finally, even though we do not observe any dramatic DNA conformational change in the presence of A beta, we do observe an increase in diversity of the DNA structural parameters such as groove width, local base step, and torsional angles in lieu of A beta interactions.

• 出版日期2015-7-2
• 单位南阳理工学院