Research Areas

G-quadruplexes are four-stranded nucleic acid structures formed by stacking of two or more G-quartets assembled via Hoogsteen base pairing. i-Motifs are formed by the stacked intercalating hemi protonated C-C base pairs (C+: C) in the cytosine-rich stretch of genomic sequences in a slightly acidic environment. These secondary structures are significant in the process of gene regulation. Potential G-quadruplex forming sequences are present in the genome's telomeres, promoters, and introns and also in the UTRs of mRNAs. Depending upon the sequence and environment, G-quadruplexes can adopt different topologies such as parallel, anti-parallel, and hybrid structures.  The complementary sequence to the G-rich genome has the potential to form i-Motif structures. The presence of i-Motif structures in the promoter and telomeric region of cancer cell lines has been reported. Our lab focuses on developing small molecule ligands specifically stabilizing a particular G-quadruplex topology for target-specific therapeutic intervention. We also develop fluorescent probes to sense G-quadruplex and i-Motif structures inside the cell. In addition, we use molecular modeling and molecular dynamics studies to decipher the binding mode of these G-quadruplex / i-Motif interacting ligands. In this line, we have published multiple parallel promoter G-quadruplex specific ligands and turn on fluorescence probe. (ACS Chem. Biol. 2019, 14, 2102–2114 (REVIEW); Biochemistry 2022, 61, 1064–1076,  ACS Chem. Biol., 2015, 10, 821–833.; Phys. Chem. Chem. Phys., 2022, 24, 6238-6255.; J. Am. Chem. Soc. 2013, 135, 367-376).

Continuous exposure to exogenous and endogenous agents leads to DNA damage. If DNA damage is not repaired, it can lead to mutation and cancer. Various carcinogens and its reactive metabolites can react with nucleophilic centers of DNA and lead to chemical modifications called DNA lesions or adducts. Such lesions can block the progress of the replication process by replicative polymerases. Polycyclic aromatic hydrocarbons and various heterocyclic aromatic amines are well known to form N2-deoxyguanosine and N6- deoxyadenosine adducts. If such lesions remain unrepaired, the cell recruits specialized DNA polymerases (belong to Y-family) to carry out Translesion Synthesis (TLS) across the lesions. TLS is the bypass of damaged sites by incorporation of a nucleotide across the damage, which can be error-free or error-prone. Understanding the role of various human TLS polymerases during the replication process in the presence of these DNA lesions is very important, but the structural and functional requirements to perform TLS are not well understood. In this connection, our laboratory focuses on developing robust chemical synthesis of various N2-modified-dG and N6-modified-dA oligonucleotides and the role of Polymerase IV from bacteria, pol kappa, pol eta and PrimPol from humans in the TLS process across these adducts. Moreover, molecular enzymology (primer extension assays),  X-ray crystallography, and molecular modeling and dynamics studies are utilized to delineate the lesion bypass abilities of polymerases. (Structure, 2015, 23, 56-67, Eur. J. Org. Chem. 2020, 6831–6844, Chem. res. toxicol. 2017, 30 , 2023-2032.,  J. Org. Chem. 2019, 84,1734–1747.)

Deoxyribozymes, also known as DNA enzymes, are single-stranded oligo-deoxyribonucleotide molecules that, like proteins and ribozymes, can catalyze various bio-organic reactions. Despite the fact that no DNA enzymes have been found in living species, they have been obtained in the laboratory using in vitro selection from large random-sequence DNA pools. Our laboratory's focus is the development, characterization, and application of DNA enzymes capable of catalyzing various biochemical reactions.  Aptamers are single-stranded nucleic acids capable of binding to various chemical and biological targets. These are discovered by in vitro selection experiments. Our lab is interested to discover new aptamers against multiple proteins involved in the antibiotic resistance pathways.

Molecular modeling and dynamics (MD) studies are valuable tools to unravel the molecular-level interactions present in nucleic acids.  Our lab focuses on the molecular modeling and dynamic studies of various functional nucleic acids like siRNAs, CRISPR RNAs, G-quadruplexes, Oxepane nucleic acids, and DNA damages (Nucleic Acids Res. 2020, 48, 4643–4657.; J. Chem. Inf. Model., 2017, 57 (4), 883–896.)

CRISPR is an adapted immune mechanism existing in bacteria against Phage infections. Over the years, CRISPR-cas complexes have been utilized as a powerful imaging and gene-editing tool in Eukaryotes. To decrease the instances of off-target cleavages and increase the efficiency of the editing the CRISPR-cas complexes need to be modified. Rational designing of these modifications has not been carried out due to the absence of structural information associated with the modified CRISPR-Cas complexes. Our lab focuses on utilizing molecular modeling and dynamics simulations to gain insights into the atomistic details to aid the rational incorporation of modifications in the Cas complexes. (J. Biol. Chem. 2023, 299, 104700.)

G-quadruplexes are four-stranded nucleic acid structures formed by stacking of two or more G-quartets assembled via Hoogsteen base pairing. Selective stabilization of G4 structures offers an attractive anticancer strategy. Our lab focuses on studying the binding modes as well as the structural features of small molecule ligands responsible for the selective stabilization of parallel G-quadruplexes utilizing molecular dynamics simulations (Biochemistry 2022, 61, 22, 2546-2549.; Phys. Chem. Chem. Phys., 2022, 24, 6238-6255.; Mol. BioSyst., 2017, 13, 1458–1468.; J. Am. Chem. Soc. 2013, 135, 367-376.) 

 Translesion synthesis or TLS is the bypass of damaged sites by incorporation of a nucleotide across the damage, BY specialized TLS polymerases, which can be error-free or error-prone. Understanding the role of various human TLS polymerases during the replication process in presence of the DNA lesions is very important, but the structural information related to this is limited. Therefore, we focus on the bypass mechanism and mode of action of the TLS polymerases across various DNA adducts with the help of molecular modeling and dynamics studies  (ACS Chem. Biol. 2022, 17, 11, 3238–3250.; J. Org. Chem. 2019, 84,1734–1747.)