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 forming 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.

Complexity of Guanine Quadruplex Unfolding Pathways Revealed by Atomistic Pulling Simulations

“…This limitation could have affected the unfolding pathways and prevented detection of important intermediates during the unfolding process. A mesoscopic model has also been developed with the aim to apply lower force loads during SMD simulations of the parallel human telomeric GQ (86). However, the simplistic nature of the model (one bead per nucleotide) led to GQ unfolding via unusual G-quartet rotations (i.e., major changes in GQ helicity) and elongations.…”