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I-Motif (iM) DNA structures represent among the most significant noncanonical nucleic acid configurations. iM-forming DNA sequences are found in an array of vital genomic locations and are particularly frequent in the promoter islands of various oncogenes. Thus, iM DNA is a crucial candidate for anticancer medicines; therefore, binding interactions between iM DNA and small molecular ligands, such as flavonoids, are critically important. Extensive sets of spectroscopic strategies and thermodynamic analysis were utilized in the present investigation to find out the favorable interaction of quercetin (Que), a dietary flavonoid that has various health-promoting characteristics, including anticancer properties, with noncanonical iM DNA structure. Spectroscopic studies and thermal analysis revealed that Que interacts preferentially with HRAS1 iM DNA compared with VEGF, BCL2 iM, and duplex DNA. Que, therefore, emerged as a suitable natural-product-oriented antagonist for targeting HRAS1 iM DNA. The innovative spectroscopic as well as mechanical features of Que and its specific affinity for HRAS1 iM may be useful for therapeutic applications and provide crucial insights for the design of compounds with remarkable medicinal properties.

Small molecule ligands-DNA interactions have recently received a lot of attention in the fields of life sciences, medicine, and chemical sciences. To decode these interactions, many strategies have been developed. DNA is the primary target for a wide range of drugs that may interact with DNA in particular or non-specific ways and impact its activities. Fluorescence spectroscopy is a highly advanced and non-invasive technology for measuring the concentrations of substrates and products or identifying characteristic processing states. Small molecule ligands-DNA interaction studies are beneficial not only in comprehending the method of interaction, but also in synthesizing DNA-targeted particular drugs. Several small compounds that bind to DNA are clinically established therapeutic medicines, while their specific mechanism of action is unknown. Figuring out their molecular recognizing patterns is the only way to construct innovative compounds that can target specific DNA sequences with strong affinities. This book chapter will mostly explore several fluorescence spectroscopic methodologies used to investigate interactions between small molecule ligands and DNA. In addition, we provide many approaches for determining a drug's binding mode with DNA. These strategies produce data that is both trustworthy and easy to comprehend. All of the knowledge gained by studying these fluorescence spectroscopies are supposed to lead to the development of more efficient new pharmaceuticals that might aid in the treatment of diseases., (© 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

In this work we study the structure-transport property relationships of small ligand intercalated DNA molecules using a multiscale modeling approach where extensive ab initio calculations are performed on numerous MD-simulated configurations of dsDNA and dsDNA intercalated with two different intercalators, ethidium and daunomycin. DNA conductance is found to increase by one order of magnitude upon drug intercalation due to the local unwinding of the DNA base pairs adjacent to the intercalated sites, which leads to modifications of the density of states in the near-Fermi-energy region of the ligand-DNA complex. Our study suggests that the intercalators can be used to enhance or tune the DNA conductance, which opens new possibilities for their potential applications in nanoelectronics.

Double-stranded DNA (dsDNA) has been established as an efficient medium for charge migration, bringing it to the forefront of the field of molecular electronics and biological research. The charge migration rate is controlled by the electronic couplings between the two nucleobases of DNA/RNA. These electronic couplings strongly depend on the intermolecular geometry and orientation. Estimating these electronic couplings for all the possible relative geometries of molecules using the computationally demanding first-principles calculations requires a lot of time and computational resources. In this article, we present a machine learning (ML)-based model to calculate the electronic coupling between any two bases of dsDNA/dsRNA and bypass the computationally expensive first-principles calculations. Using the Coulomb matrix representation which encodes the atomic identities and coordinates of the DNA base pairs to prepare the input dataset, we train a feedforward neural network model. Our neural network (NN) model can predict the electronic couplings between dsDNA base pairs with any structural orientation with a mean absolute error (MAE) of less than 0.014 eV. We further use the NN-predicted electronic coupling values to compute the dsDNA/dsRNA conductance.

In this study, we compare the charge transport properties of multiple double-stranded (ds)RNA sequences with corresponding dsDNA sequences. Recent studies have presented a contradictory picture of relative charge transport efficiencies in A-form DNA : RNA hybrids and dsDNA. Using a multiscale modelling framework, we compute conductance of dsDNA and dsRNA using Landauer formalism in the coherent limit and Marcus-Hush theory in the incoherent limit. We find that dsDNA conducts better than dsRNA in both the charge transport regimes. Our analysis shows that the structural differences in the twist angle and slide of dsDNA and dsRNA are the main reasons behind the higher conductance of dsDNA in the incoherent hopping regime. In the coherent limit however, for the same base pair length, the conductance of dsRNA is higher than that of dsDNA for the morphologies where dsRNA has a smaller end-to-end length relative to that of dsDNA.

Charge transport in deoxyribonucleic acid (DNA) is of immense interest in biology and molecular electronics. Electronic coupling between the DNA bases is an important parameter describing the efficiency of charge transport in DNA. A reasonable estimation of this electronic coupling requires many expensive first principle calculations. In this article, we present a machine learning (ML) based model to calculate the electronic coupling between the guanine bases of the DNA (in the same strand) of any length, thus avoiding expensive first-principle calculations. The electronic coupling between the bases are evaluated using density functional theory (DFT) calculations with the morphologies derived from fully atomistic molecular dynamics (MD) simulations. A new and simple protocol based on the coarse-grained model of the DNA has been used to extract the feature vectors for the DNA bases. A deep neural network (NN) is trained with the feature vector as input and the DFT-calculated electronic coupling as output. Once well trained, the NN can predict the DFT-calculated electronic coupling of new structures with a mean absolute error (MAE) of 0.02 eV.

Inherent molecular fluctuations are known to have a significant influence on the charge transport properties of biomolecules like DNA, PNA and proteins. In this work, we show ways to control these fluctuations and further demonstrate their use to enhance the conductance of two widely studied molecular wires, namely dsDNA (DNA) and G4 Quadruplex (G4-Quad). We quantify the molecular fluctuation in terms of the root mean square deviation (RMSD) of the molecule. In the case of DNA, we use temperature to control the fluctuations, while in the case of G4-Quad the fluctuations are tuned by the ions inside the pore. The electronic coupling between the bases of dsDNA and G4-Quad, which measures the conductance of these molecular wires, shows a non-monotonic behaviour with the increase in fluctuation. We find values of fluctuation which give rise to maximum electronic coupling and hence high conductivity for both the cases. In the case of DNA, these optimal fluctuations (∼2.5 Å) are achieved at a temperature of 210 K, which gives rise to an electronic coupling of 0.135 eV between the DNA bases. The optimal fluctuations in G4-Quad are achieved (∼7 Å) in a 4 base pair long system with 2 Na + ions inside the pore, giving rise to an electronic coupling of 0.09 eV.

In spite of the striking difference between twist-stretch coupling of dsRNA and dsDNA under external force, dsRNA shows similar structural polymorphism to dsDNA under different pulling protocols. Our atomistic MD simulations show that overstretching dsRNA along the 3' direction of the opposite strands (OS3) leads to the emergence of S-RNA whereas overstretching along the 5' directions of the opposite strands (OS5) leads to melting of dsRNA at lower forces. Using the dsRNA morphology from pulling MD simulations, we use a multiscale method involving ab initio calculations and Kinetic Monte Carlo (KMC) simulations to estimate the conductance of dsRNA and find that the conformational changes drastically affect its conductance. The current through dsRNA chains drastically drops after a critical stretching length and critically depends on the pulling protocol. The critical stretching length for the OS3 pulling case is around 65% higher than that of the OS5 case.

In order to interpret recent experimental studies of the dependence of conductance of ds-DNA as the DNA is pulled from the 3'end1-3'end2 ends, which find a sharp conductance jump for a very short (4.5%) stretching length, we carried out multiscale modeling to predict the conductance of dsDNA as it is mechanically stretched to promote various structural polymorphisms. We calculate the current along the stretched DNA using a combination of molecular dynamics simulations, non-equilibrium pulling simulations, quantum mechanics calculations, and kinetic Monte Carlo simulations. For 5'end1-5'end2 attachments we find an abrupt jump in the current within a very short stretching length (6 Å or 17%) leading to a melted DNA state. In contrast, for 3'end1-3'end2 pulling it takes almost 32 Å (84%) of stretching to cause a similar jump in the current. Thus, we demonstrate that charge transport in DNA can occur over stretching lengths of several nanometers. We find that this unexpected behaviour in the B to S conformational DNA transition arises from highly inclined base pair geometries that result from this pulling protocol. We found that the dramatically different conductance behaviors for two different pulling protocols arise from how the hydrogen bonds of DNA base pairs break.

To explore the natural microbial community of any ecosystems by high-resolution molecular approaches including next generation sequencing, it is extremely important to develop a sensitive and reproducible DNA extraction method that facilitate isolation of microbial DNA of sufficient purity and quantity from culturable and uncultured microbial species living in that environment. Proper lysis of heterogeneous community microbial cells without damaging their genomes is a major challenge. In this study, we have developed an improved method for extraction of community DNA from different environmental and human origin samples. We introduced a combination of physical, chemical and mechanical lysis methods for proper lysis of microbial inhabitants. The community microbial DNA was precipitated by using salt and organic solvent. Both the quality and quantity of isolated DNA was compared with the existing methodologies and the supremacy of our method was confirmed. Maximum recovery of genomic DNA in the absence of substantial amount of impurities made the method convenient for nucleic acid extraction. The nucleic acids obtained using this method are suitable for different downstream applications. This improved method has been named as the THSTI method to depict the Institute where the method was developed.