Tracking Topological and Electronic Effects on the Folding and Stability of Guanine-Deficient RNA G-Quadruplexes, Engineered with a New Computational Tool for De Novo Quadruplex Folding

Int J Mol Sci. 2022 Sep 20;23(19):10990. doi: 10.3390/ijms231910990.


The initial aim of this work was to elucidate the mutual influence of different single-stranded segments (loops and caps) on the thermodynamic stability of RNA G-quadruplexes. To this end, we used a new NAB-GQ-builder software program, to construct dozens of two-tetrad G-quadruplex topologies, based on a designed library of sequences. Then, to probe the sequence-morphology-stability relationships of the designed topologies, we performed molecular dynamics simulations. Their results provide guidance for the design of G-quadruplexes with balanced structures, and in turn programmable physicochemical properties for applications as biomaterials. Moreover, by comparative examinations of the single-stranded segments of three oncogene promoter G-quadruplexes, we assess their druggability potential for future therapeutic strategies. Finally, on the basis of a thorough analysis at the quantum mechanical level of theory on a series of guanine assemblies, we demonstrate how a valence tautomerism, triggered by a coordination of cations, initiates the process of G-quadruplex folding, and we propose a sequential folding mechanism, otherwise dictated by the cancellation of the dipole moments on guanines.

Keywords: RNA G-quadruplex folding; RNA G-quadruplex stabilization; RNA—cation interactions; de novo RNA modelling; valence tautomerism.

MeSH terms

  • Biocompatible Materials
  • Cations / chemistry
  • Electronics
  • G-Quadruplexes*
  • Guanine / chemistry


  • Biocompatible Materials
  • Cations
  • Guanine