As the main carrier of genetic information, deoxyribonucleic acid (DNA) is a crucial component of virtually all living cells. It has been known for some time now that besides its well-known double helix form, the molecule can also form a number of other secondary structures with interesting biological functionalities.
Similarly to proteins, the final fold assumed by the DNA strand might depend on the sequence. To date, multiple experiments have shown that also the external conditions – temperature, pressure, molecular crowding, pH and salt content – can shift the equilibrium between the folded and unfolded state, as well as between different folded conformations. G-quadruplexes are one of such secondary structures assumed by DNA. These structures possess a distinctive biological activity and are found in genomic DNA of active cells. Since their actual biological role is not well understood, they are being extensively studied, in part as potential targets for cancer therapies. Such applicational potential stems from the role of G-quadruplexes in regulation of replication and transcription, as well as maintenance of genomic integrity. It has been found that 10% of the G4s present in cells are formed within the guanine-rich single-stranded 3'-overhang present on the termini of linear chromosomes, in the telomeric regions.
A common structural motif assumed by all G-quadruplexes is the core composed of several guanine planes (tetrads) stacked one upon the other. Each of these planes consists of 4 guanine residues joined together by Hoogsteen-type hydrogen bonds. In unimolecular quadruplexes, the guanine planes are kept in fixed position by the remaining portions of the DNA strand, forming loops of different topology. For these reasons, such an arrangement can only be formed by sequences matching the GnXGnXGnXGn template, with n being the number of tetrads forming the structure, and X being any combination of loop-forming nucleotides. Monovalent metal ions, located e.g. in the central channel between the planes, have also been implicated in conferring the stability of G-quadruplexes.
Our research aims to understand the molecular basis of G-quadruplex stability in physiological conditions. We wish to identify the forces that drive the formation of different G4 topologies, with particular focus on the role of indivitual components (tetrads, loops, ions and solvent) in determining the stability of the given fold. The broader goal is to achieve a molecular-level understanding of the mechanisms and thermodynamics of conformational changes between individual DNA structures, which is a prerequisite for any attempt to control them externally, e.g. using specifically designed molecules.
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