Polymeric Properties of Higher-Order G-Quadruplex Telomeric Structures: Effects of Chemically Inert Crowders

TL;DR

This study introduces a novel coarse-grained model to analyze the flexibility and polymeric behavior of G-quadruplex DNA structures, revealing their chain stiffness and effects of crowding, with implications for anticancer drug design.

Contribution

It presents a new modeling approach that captures the structural flexibility of G-quadruplexes and investigates their behavior under crowded conditions, advancing understanding of their biological functions.

Findings

G-quadruplex multimers are flexible polymers with local persistence length similar to monomers.

Crowding increases G-quadruplex coiling and decreases chain stiffness.

Accurate polymeric modeling aids in designing effective G4-targeting anticancer drugs.

Abstract

G-quadruplexes are non-canonical DNA structures rather ubiquitous in human genome, which are thought to play a crucial role in the development of 85-90 % of cancers. Here, we present a novel coarse-grained approach in modeling G-quadruplexes which accounts for their structural flexibility. We apply it to study the polymeric properties of G-quadruplex multimers, with and without crowder particles, to mimic in-vivo conditions. We find that, contrary to some suggestions found in the literature, long G-quadruplex multimers are rather flexible polymeric macromolecules, with a local persistence length comparable to monomer size, exhibiting chain stiffness variation profile consistent with a real polymer in good solvent. Moreover, in a crowded environment (up to 10% volume fraction), we report that G-quadruplex multimers exhibit an increased propensity for coiling, with a corresponding decrease in the measured chain stiffness. Accurately accounting for the polymeric properties of G4 multimers is crucial for understanding their interactions with anticancer G4-targeting drugs, thereby significantly enhancing the design and effectiveness of these drugs.