Resolving a guanine-quadruplex structure in the SARS-CoV-2 genome through circular dichroism and multiscale molecular modeling

Abstract

Parallel or hybrid? A combination of multiscale molecular modeling and circular dichroism is used to predict a G-quadruplex structure at atomistic resolution in the SARS-CoV-2 genome.

Resolving the Structure of a Guanine Quadruplex in TMPRSS2 Messenger RNA by Circular Dichroism and Molecular Modeling

“…Specifically, the presence of a strong positive ellipticity at 260 nm, as well as a negative one at 240 nm align well with previous findings reported and notably supports the parallel conformation of the G4. [6] As it can be appreciated from Figure 2, when considering a global shift of the excitation wavelengths, coherently with our previous work, [5,17] we recover a band shape which is almost totally superposable with the experimental one. Of note, the slight overestimation of the negative peak in the computed spectrum is due to the truncation of the modelled excited states.…”

“…using a protocol developed by us, and used to determine the structure of SARS-CoV-2 G4. [5,17] This protocol involves, as the first step, the sequence reconstruction by homology modelling.…”

“…[4] This is also probably due to the inherent more pronounced instability of RNA sequences, which complicates their precise structural resolution. [5] G4 tend to accumulate in guanine-rich regions of the genome, and as such are particularly present in the telomeric caps. [6][7][8] Their capacity to inhibit telomerase [9] contributes to the regulation of cell cycle and the entry in senescence, avoiding the emergence of the immortality phenotype typical of cancer cells.…”

“…[10,11] While usually the presence of stable and persistent G4 is correlated with gene silencing, in some instances, such as vascular epithelial growth factor (VEGF), G4 structures are able to recruit transcription factors, hence favoring gene expression. [12,13] Recently, the presence of G4 has also been identified in viral genomes, including DNA viruses, retroviruses, such as human immunodeficiency virus (HIV), [14][15][16] and RNA viruses, including SARS-CoV-2, [5,[17][18][19] Zika, [20] and other flaviviruses, making them also ideal targets for novel antiviral therapies. [21,22] Furthermore, the presence of G4 in RNA viral genomes, also proves the importance of these non-canonical arrangement in the framework of RNA regulation.…”

The Rise of Bacterial G-Quadruplexes in Current Antimicrobial Discovery

“…Structure prediction tools such as homology modeling and AlphaFold fail to work with nucleic acids structural templates. Nevertheless, some attempts to predict the structure of a G4 by coupling spectroscopic data (see below) with the structures of relatively similar sequences have been carried out. − Anyway, the availability of bacterial G4s structures still represents a major drawback in G4-oriented drug design.…”