Abstract Quadruplexes are four-stranded nucleic acid secondary structures that play diverse biological roles. A recent meticulous analysis of known quadruplex structures formed from synthetic oligonucleotides shows that quadruplexes can adopt 33 distinct structural motifs (pairs of stacked quartets) that serve as scaffolds for simple (multi-layered quartets) and complex (multi-motifs) quadruplex folds. These motifs differ from one another in terms of interstrand connectivity and orientation. Interstrand connectivity is primarily governed by diagonal loops that connect alternate strands and lateral and propeller loops that connect adjacent strands. These loops are absent in tetramers, wherein interstrand orientation alone dictates the motif type. While the diversity of potential quadruplex-forming sequences, enriched in functionally important regions of the human genome, implicates their structural diversity, a key question that still remains unresolved is the complete landscape of quadruplex folds. For the first time, a total of 156 unique theoretically possible quadruplex motifs that cover the quadruplex fold landscape are mathematically devised here. Given the difficulty in capturing the transient quadruplex intermediates that mediate the quadruplex folding process, the folds reported here may shed light on the possible quadruplex intermediates. A tool named 3D-NuS-Qplex (https://project.iith.ac.in/3d-nus-qplex/) has also been developed to model all the theoretically possible energy-minimized quadruplex folds with options to incorporate overhangs and non-G-quartets (in addition to G-quartets) in both DNA and RNA contexts. The diversity of quadruplex folds reported here provides new insight into their structural complexity, which appears greater than previously anticipated, and may thus facilitate understanding of quadruplex folding, quadruplex–protein, and quadruplex–ligand interactions.
Rathinavelan et al. (Fri,) studied this question.