Abstract
By using all atom molecular dynamics simulations, we studied the behavior of human DNA telomere sequences in guanine quadruplex (G4) conformation and in the presence of oxidative lesions, namely abasic sites. In particular, we evidenced that while removing one guanine base induces a significant alteration and destabilization of the involved leaflet, human telomere oligomers tend, in most cases, to maintain at least a partial quadruplex structure, eventually by replacing the empty site with undamaged guanines of different leaflets. This study shows that (i) the disruption of the quadruplex leaflets induces the release of at least one of the potassium cations embedded in the quadruplex channel and that (ii) the electrostatic interactions of the DNA sequence with the aforementioned cations are fundamental to the maintenance of the global quadruplex structure.
Highlights
DNA is the essential biological macrostructure responsible for the storing, replication, and transduction of the genetic information of living organisms
In the case of the AP site, we consistently used the same parameters as the ones obtained in our previous work [29,52] and built the replicas, using the standard amber procedure based on the restrained electrostatic potential (RESP) [53,54] protocol
Despite a more pronounced restructuration compared to the one experienced by the other members of this class, even the 4G oligomer maintained two stable tetrads
Summary
DNA is the essential biological macrostructure responsible for the storing, replication, and transduction of the genetic information of living organisms. As such, maintaining its chemical structure is essential to avoid genome instability that can lead either to cell death or to the development of mutations. DNA is constantly exposed to a number of endogenous or exogeneous stress sources [1] that may trigger chemical reactions resulting in the modification of its structure, i.e., DNA damage or lesions [2]. As a non-exhaustive list of stress sources, one can cite reactive oxygen species (ROS) produced by the cellular metabolism or by external agents [3,4] as well as ionization radiation [5], pollutants [6], or the exposure to UV light [7,8]. Different stress agents produce specific classes of lesions that may involve DNA nucleobases or the phosphate and sugar backbone components. The accumulation of DNA lesions, due to the imbalance between their production and repair, is related to the emergence of seriously debilitating diseases, such as cancers [9,10]
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