Mesoscopic model for DNA G-quadruplex unfolding

Abstract

Genomes contain rare guanine-rich sequences capable of assembling into four-stranded helical structures, termed G-quadruplexes, with potential roles in gene regulation and chromosome stability. Their mechanical unfolding has only been reported to date by all-atom simulations, which cannot dissect the major physical interactions responsible for their cohesion. Here, we propose a mesoscopic model to describe both the mechanical and thermal stability of DNA G-quadruplexes, where each nucleotide of the structure, as well as each central cation located at the inner channel, is mapped onto a single bead. In this framework we are able to simulate loading rates similar to the experimental ones, which are not reachable in simulations with atomistic resolution. In this regard, we present single-molecule force-induced unfolding experiments by a high-resolution optical tweezers on a DNA telomeric sequence capable of adopting a G-quadruplex conformation. Fitting the parameters of the model to the experiments we find a correct prediction of the rupture-force kinetics and a good agreement with previous near equilibrium measurements. Since G-quadruplex unfolding dynamics is halfway in complexity between secondary nucleic acids and tertiary protein structures, our model entails a nanoscale paradigm for non-equilibrium processes in the cell.

Structure of human telomere G-quadruplex in the presence of a model drug along the thermal unfolding pathway

“…At the highest temperatures, a completely unfolded state is attained, characterized by the absence of any stacking between the bases of the oligonucleotide and a spatial arrangement consistent with that of a nucleotide chain obeying the self-avoiding walk statistics (47). Both the values of R g for the native and the unfolded states are in agreement with the estimate provided by the mesoscopic model of G-quadruplex thermal stability (54).…”

G-Quadruplex and I-Motif Structures within the Telomeric DNA Duplex. A Molecular Dynamics Analysis of Protonation States as Factors Affecting Their Stability

“…These noncanonical DNA structures that is, i-motif ,,− and G-quadruplex, ,,− have recently been carefully studied using either experimental or computational techniques. − However, in majority of cases these structures were studied separately and as short individual fragments. To our best knowledge, theoretical studies of these secondary structures were always limited to individually existing short sequences of telomeric DNA.…”

Role of fast dynamics in the complexation of G-quadruplexes with small molecules

“…This distance has been estimated according to the crystal structure of the human telomeric parallel G4. 44 We can then write: ffiffiffiffiffiffiffiffiffiffiffiffiffi r 2 h i unf q ¼ 0:17L t…”