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

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Июль 30, 2024

Abstract The presence of a guanine quadruplex in the opening reading frame messenger RNA coding for transmembrane serine protease 2 (TMPRSS2) may pave way to original anticancer and host-oriented antiviral strategy. Indeed, TMPRSS2 addition being overexpressed different cancer types, is also related infection respiratory viruses, including SARS-CoV-2, by promoting cellular viral membrane fusion through its proteolytic activity. design selective ligands targeting requires detailed knowledge, at atomic level, structure. Therefore, we have used an experimental-computational protocol predict first resolved structure parallel secondary TMPRSS2, which shows rigid core flanked flexible loop. This represents scale present RNA.

Язык: Английский

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Machine learning-based prediction of DNA G-quadruplex folding topology with G4ShapePredictor

Scientific Reports, Год журнала: 2024, Номер 14(1)

Опубликована: Окт. 16, 2024

Deoxyribonucleic acid (DNA) is able to form non-canonical four-stranded helical structures with diverse folding patterns known as G-quadruplexes (G4s). G4 topologies are classified based on their relative strand orientation following the 5' 3' phosphate backbone polarity. Broadly, either parallel (4+0), antiparallel (2+2), or hybrid (3+1). G4s play crucial roles in biological processes such DNA repair, replication, transcription and have thus emerged targets drug design. While computational models been developed predict formation, there currently no existing model capable of predicting topology its nucleic sequence. Therefore, we introduce G4ShapePredictor (G4SP), an application featuring a collection multi-classification machine learning that trained custom dataset combining entries from literature in-house circular dichroism experiments. designed accurately potassium (

Язык: Английский

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In Silico Design of a Solution-Gated Graphene Transistor Sensor for the Efficient Detection of Guanine Quadruplexes

The Journal of Physical Chemistry Letters, Год журнала: 2024, Номер 15(43), С. 10881 - 10887

Опубликована: Окт. 23, 2024

Guanine quadruplexes (G4s) are nucleic acid structures present in diverse regions of the genome, such as telomeres and transcription initiators. Recently, different biological roles G4s have been evidenced well their role biomarkers for tumors or viral infections. However, fast efficient detection complex matrices remains elusive. In this contribution, by using long-scale molecular dynamics simulations, we propose design a biosensor based on organic field-effect transistors recognizing G4s. particular, show that interaction with is translated into change charge density profile, which correlates electrical transduction signal, thus allowing structure. We also provide rules thumb optimization device more generally integration computationally driven approaches.

Язык: Английский

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Rationally Designed G-Quadruplex Selective “Turn-On” NIR Fluorescent Probe with Large Stokes Shift for Nucleic Acid Research-Based Applications

ACS Applied Bio Materials, Год журнала: 2024, Номер 7(11), С. 7233 - 7243

Опубликована: Окт. 28, 2024

Guanine-rich DNA/RNA sequences can form Hoogsteen bonds to adopt noncanonical secondary structures called G-quadruplexes, and these have been associated with diverse cellular processes. There has considerable research interest in the design of G4-interacting ligands for probing G4 structure understanding its biological function. Most fluorescent either do not significant selectivity over other nucleic acid structures, high Stokes shift, or are near-infrared (NIR) region, which limits visualization. The current work involves rational synthesis NIR probes comprising a (Z)-1-methyl-2-((3-methylbenzo[d]thiazol-2(3H)-ylidene)methyl)quinolin-1-ium scaffold. Among designed molecules, 4a exhibited far-red fluorescence (λmax = 680 nm) large shift (∼182 upon selective binding human telomeric G-quadruplexes. dye does disturb conformation stability thereby making it suitable based applications. Interestingly, showed remarkable single- double-stranded contrast commercially available quadruplex probe, Thiazole orange (TO). molecular docking studies indicate that binds at groove region DNA G-quadruplex through π–π stacking interactions quinoline amine-substituted phenyl ring phosphate backbone anion−π benzothiazole ring. molecule interesting photophysical properties, cell permeability, biocompatibility minimal cytotoxicity. Fluorescence imaging live HeLa cells probe transient population nucleus RNA quadruplexes cytoplasm. In brief, higher signal/noise ratio potential thus opens avenues decipher pathways better biology.

Язык: Английский

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Molecular Modelling and Investigation of Bioactive Stable DNA G-Quadruplex d(G4T4G4) under Different Physiological Conditions using Molecular Dynamics Simulation

Prabha Materials Science Letters, Год журнала: 2024, Номер 4(1), С. 107 - 118

Опубликована: Дек. 27, 2024

We are reporting a molecular dynamics study on the structure and conformation of DNA quadruplex. The single molecule quadruplex's coordinates were obtained modeled using PDB ID 1d59. simulation's sequence is d(GGGGTTTTGGGG). In beginning, two hairpin structures constructed with loops holding thymine residues at either end, forming four-stranded helical structure. cyclic hydrogen bonds created by kept guanine all four strands in one plane. was subjected to simulation for 100ns periodic intervals 10ns, dynamical pathway's trajectory examined. deviations fluctuations viz. RMSD, RMSF Rg plots analyzed, shape time-evolved outcome compared crystal Our findings reveal few peculiar properties which we have discussed this paper. helix axis torsion angle parameters calculated. results interpretation give idea about quadruplex interaction external agents inspire do further research telomeric regions living chromosomes.

Язык: Английский

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