Telomeric G-quadruplex and i-motif containing DNA fragments. Structure, stability and interaction with carbon nanotubes analyzed by means of molecular dynamics simulations

The noncanonical DNA structures that is, i-motif (iM) and G-quadruplex (Gq) have recently been carefully studied using either experimental or computational techniques. This is because the biological role of these structures appears to be more and more important as the research on them continues. The G-quadruplex stabilizing ligands are considered as selective inhibitors of cancer cell growth and it strongly suggests that induction of telomere shortening is a viable therapeutic strategy against cancer. Biological role of i-motif is less recognized and it was believed that it can form only at reduced pH when the semi-protonated cytosine pairs can form. G-quadruplex and i-motif are coupled in some way since they may form in the complementary regions of genome. However, in majority of cases these structure were studied independently and conclusions concerning their stabilization were rather limited to such factors like temperature, pH, presence of cations or molecular crowding conditions. Thus, in this work we are analyzing the DNA fragments with both G-quadruplex and i-motif present in the same place (iG structure). The studies are based on biased molecular dynamics in order to overcome energetic barriers associated with the structural transitions of both Gq and iM. We found that unprotonated iM is unstable in normal conditions though the presence of complementary Gq stabilizes iM or strongly retards its decay. Functionalized carbon nanotubes bind to iG structure strongly in the junction between duplex and Gq and iM. It is interesting that carbon nanotubes attack the iG structure with their tip sides which are functionalized by guanine containing residues. Removal of those functional groups leads to nonspecific binding of these compounds. This is useful information in construction of novel smart drug delivery systems which can selectively attack the cancer cells nuclei. Acknowledgments: This work was supported by Polish National Science Centre grant 2017/27/B/ST4/00108.