G-quadruplexes (G4 s), as non-canonical DNA structures, attract a great deal of research interest in the molecular biology as well as in the material science fields. The use of small molecules as ligands for G-quadruplexes has emerged as a tool to regulate gene expression and telomeres maintenance. Meso-tetrakis-(N-methyl-4-pyridyl) porphyrin (TMPyP4) was shown as one of the first ligands for G-quadruplexes and it is still widely used. We report an investigation comprising molecular docking and dynamics, synthesis and multiple spectroscopic and spectrometric determinations on simple cationic porphyrins and their interaction with different DNA sequences. This study enabled the synthesis of tetracationic porphyrin derivatives that exhibited binding and stabilizing capacity against G-quadruplex structures; the detailed characterization has shown that the presence of amide groups at the periphery improves selectivity for parallel G4 s binding over other structures. Taking into account the ease of synthesis, 5,10,15,20-tetrakis-(1-acetamido-4-pyridyl) porphyrin bromide could be considered a better alternative to TMPyP4 in studies involving G4 binding.

• Keywords
• DNA, G-quadruplexes, Molecular dynamics, Molecular recognition, NMR,
• MeSH
• Circular Dichroism MeSH
• DNA * chemistry   MeSH
• G-Quadruplexes * MeSH
• Ligands MeSH
• Porphyrins * chemistry   MeSH
• Molecular Dynamics Simulation MeSH
• Molecular Docking Simulation * MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• DNA * MeSH
• Ligands MeSH
• Porphyrins * MeSH
• tetra(4-N-methylpyridyl)porphine MeSH Browser

We have carried out an extended set of standard and enhanced-sampling MD simulations (for a cumulative simulation time of 620 μs) with the aim to study folding landscapes of the rGGGUUAGGG and rGGGAGGG parallel G-hairpins (PH) with propeller loop. We identify folding and unfolding pathways of the PH, which is bridged with the unfolded state via an ensemble of cross-like structures (CS) possessing mutually tilted or perpendicular G-strands interacting via guanine-guanine H-bonding. The oligonucleotides reach the PH conformation from the unfolded state via a conformational diffusion through the folding landscape, i.e. as a series of rearrangements of the H-bond interactions starting from compacted anti-parallel hairpin-like structures. Although isolated PHs do not appear to be thermodynamically stable we suggest that CS and PH-types of structures are sufficiently populated during RNA guanine quadruplex (GQ) folding within the context of complete GQ-forming sequences. These structures may participate in compact coil-like ensembles that involve all four G-strands and already some bound ions. Such ensembles can then rearrange into the fully folded parallel GQs via conformational diffusion. We propose that the basic atomistic folding mechanism of propeller loops suggested in this work may be common for their formation in RNA and DNA GQs.

• MeSH
• G-Quadruplexes * MeSH
• Guanine chemistry   metabolism   MeSH
• Kinetics MeSH
• RNA chemistry   metabolism   MeSH
• RNA Folding * MeSH
• Base Sequence MeSH
• Molecular Dynamics Simulation MeSH
• Thermodynamics MeSH
• Hydrogen Bonding MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Guanine MeSH
• RNA MeSH