How Divalent Cations Interact with the Internal Channel Site of Guanine Quadruplexes

Abstract

The formation of guanine quadruplexes (GQ) in DNA is crucial in telomere homeostasis and regulation of gene expression. Pollution metals can interfere with these DNA superstructures upon coordination. In this work, we study the affinity of the internal GQ channel site towards alkaline earth metal (Mg2+, Ca2+, Sr2+, and Ba2+), and (post‐)transition metal (Zn2+, Cd2+, Hg2+, and Pb2+) cations using density functional theory computations. We find that divalent cations generally bind to the GQ cavity with a higher affinity than conventional monovalent cations (e. g. K+). Importantly, we establish the nature of the cation‐GQ interaction and highlight the relationship between ionic and nuclear charge, and the electrostatic and covalent interactions. The covalent interaction strength plays an important role in the cation affinity and can be traced back to the relative stabilization of cations’ unoccupied atomic orbitals. Overall, our findings contribute to a deeper understanding of how pollution metals could induce genomic instability.

Life in Multi-Extreme Environments: Brines, Osmotic and Hydrostatic Pressure─A Physicochemical View

“…Comparison with the 250 mM Mg­(ClO 4 ) 2 data showed that the perchlorate anion, ClO 4 – , has a slightly destabilizing effect compared to Cl – , probably due to weak interactions of this highly polarizable anion with nucleic acid bases . Not only salts but also organic osmolytes such as TMAO and crowding agents like Ficoll increased the stability and thus the melting temperature of the B-DNA, but the mechanism of stabilization may vary and depend on the concentration of the cosolute. − …”

“…The carbonylic oxygens of the guanine bases define a partially negatively charged channel in the core of G4Qs which, under biological conditions, host the monovalent alkali cations K + or Na + . Principally, divalent cations can also bind to the G4Qs’ cavity, even with higher affinity compared to conventional monovalent cations owing to more favorable electrostatic and orbital interactions . Displacement of the monovalent cations in vivo could lead to genotoxicity due to structural perturbation of telomeric and promotor regions, however.…”

“…Principally, divalent cations can also bind to the G4Qs' cavity, even with higher affinity compared to conventional monovalent cations owing to more favorable electrostatic and orbital interactions. 203 Displacement of the monovalent cations in vivo could lead to genotoxicity due to structural perturbation of telomeric and promotor regions, however. We found that the telomeric G-rich sequence, which is complementary to the i-motif sequence discussed above, adopts a stable antiparallel conformation in the presence of salt already at low millimolar concentrations (SI, Figure S12), which was also stable at low temperature and against pressurization up to the kbar range.…”

Structural Insights into the Antiparallel G-Quadruplex in the Presence of K+ and Mg2+ Ions

“…Mg 2+ cations were found capable of placing themselves in the plane of the AGQ tetrad with a high binding ability compared to K + , which places itself in between the two tetrad planes. Several studies established that in the presence of cations, the guanine tetrad possesses extra stabilization energy, which results due to the change in its electronic environment. − Since all-atomic MD simulation is insufficient to capture the charge delocalization, the hybrid QM/MM (quantum mechanical/molecular mechanical) MD simulations were performed. First two guanine tetrads of AGQ with the necessary metal ions (2 Mg 2+ ions3MAGQ, 1 K + ion2KAGQ, no cationAPO-AGQ) were treated with the SCC–DFTB level of QM theory, and the rest of the system was handled classically; atomic-level details of the QM region are shown in Figure A.…”

How the Chalcogen Atom Size Dictates the Hydrogen‐Bond Donor Capability of Carboxamides, Thioamides, and Selenoamides

“…These planar structures furnish identical hydrogen‐bond energy trends as the non‐planar C 1 complexes (see Tables S2 and S3). The use of planar geometries allows for the separation of interactions within the σ and π electronic system which will become useful later on in this work [13b,f,14,15] …”