A couple of months ago, I came across the homepage of the newly-established G4 Society on G-quadruplexes (G4s). I checked the “Online tools” section and found a few links to G4 databases and sequence-based predication programs (e.g., G4Hunter). No tools, however, were listed for G4 identification and characterization from 3D atomic coordinates as those deposited in the Protein Data Bank (PDB). So I filled out the contact form and provided a brief description of 3DNA-DSSR, including a link to the website of G4s auto-curated with DSSR from the PDB.

I’ve recently visited the G4-society website again. I am pleased to see that 3DNA-DSSR is now listed under Online tools as a “program for detections/annotations of G4 from atomic coordinates in PDB or PDBx/mmCIF format”. The G4 module of 3DNA-DSSR has been created to streamline the identification and annotation of 3D structures of G4s. The collection of G4s in the PDB, available at G4.x3dna.org, is updated weekly. It represents a unique resource for the G4 community. Hopefully, its value will be more widely appreciated thanks to the link from the G4-society website.

At the G4-society homepage, I noticed the following two items in the “News” section (on December 13, 2019):

The Quadruplex Meeting Report

Meeting report: Seventh International Meeting on Quadruplex Nucleic Acids (Changchun, P.R. China, September 6e9, 2019) written by Jean-Louis Mergny. Reading through the report, I noticed the following:

Jonathan B. Chaires (U. Louisville, KY, USA) provided an overview and historical perspective of the quadruplex field in his inaugural lecture. As of August 2019, the quadruplex field gathers 8467 articles and 253,174 citations in the Science Citation Index. Over 200 G4 structures are available in the PDB.

I did not know how the survey of G4s in the PDB was performed. Based on my data, the PDB-G4 structures was already over 300 as of August 2019. As of December 11, 2019, the number of G4 structures in the PDB is 329. Importantly, the PDB-G4 website compiled using 3DNA-DSSR contains not only citation information but also detailed annotations and schematic images not available elsewhere. Here are a few recent examples:

• PDB id: 6ge1 — “Unraveling the structural basis for the exceptional stability of RNA G-quadruplexes capped by a uridine tetrad at the 3’ terminus.” by Andralojc et al. in RNA (2019).

• PDB id: 6gh0 — “Two-quartet kit* G-quadruplex is formed via double-stranded pre-folded structure.” by Kotar et al. in Nucleic Acids Res. (2019).

• PDB id: 6e8u — “Structure and functional reselection of the Mango-III fluorogenic RNA aptamer.” by Trachman et al. in Nat. Chem. Biol. (2019).

• PDB id: 6ac7 —“Structure of a (3+1) hybrid G-quadruplex in the PARP1 promoter.” by Sengar et al. in Nucleic Acids Res. (2019).

The Important Paper

A guide to computational methods for G-quadruplex prediction by Emilia Puig Lombardi and Arturo Londoňo-Vallejo in Nucleic Acids Res. (2019), which presents an updated overview of G4 prediction algorithms. I am impressed by the large number of sequence-based G4 prediction software tools, including the most recent G4-iM Grinder. Nevertheless, as noted by the authors in the concluding remarks, “All computational G-quadruplex prediction approaches have their drawbacks and limitations despite the recent advances in the field and the introduction of validation steps based on experimental data.”

The G4 module in 3DNA-DSSR belongs to a completely different category of software tool. It does not ‘predict’ G4 propensity/stability from a base sequence, but identify and annotate G4s in a 3D atomic coordinate file. It complements sequence-based predicting tools by gaining insights into the 3D G4 structures and refining folding rules to improve performance of prediction tools. Based on my knowledge, the 3D G4 structures contains features that are not captured by any of the sequence-based prediction tools.

While reading the review article, I found Fig. 1 informative (see below). The right side of Fig. 1A shows a “cartoon representation of the Oxytricha telomeric DNA G4 crystal structure (PDB accession 1JPQ (112))” using PyMOL. In comparison, the cartoon-block image auto-generated via 3DNA-DSSR and PyMOL for PDB id: 1jpq is shown at the bottom. The DSSR-PyMOL version is obviously different, presumably simpler and more informative, from that illustrated in Fig. 1A.