Molecular Biophysics Lab

Research

Short tandem repeats in the eukaryotic genome, which are 1 to 6 nucleotide(s) in length, are frequently observed. Abnormal expansion of these short tandem repeats destabilizes the secondary structure and subsequently triggers the formation of unusual (non-B-DNA) nucleic acid conformations. Most of these unusual conformations are associated with tri-nucleotides (or triplet repeats) such as CAG•CTG, CGG•CCG and GAC•GTC repeats that cause major genetic instability. Triplet repeats are associated with over 22 incurable neurological and neuromuscular disorders like Huntington’s disease (CAG•CTG repeats), fragile X syndrome (CGG•CCG), skeletal dysplasia (GAC•GTC), Frederick’s ataxia (GAA•TTC) etc. These repeats are found throughout the genome and form unusual conformations such as hairpin structure, G-quadruplexes and i-motif structures which contain non-canonical base pairs. The diseases can be targeted either at DNA or RNA or RNA.DNA hybrid or protein level.

Our study aims to understand the mechanical properties of DNA (or RNA) and its conformational dynamics while interacting with protein using molecular biology, single-molecule biophysics and molecular dynamics (MD) simulations methods.

Research interests: Nucleic acid structure and dynamics, DNA-Protein Interactions, RNA-Protein Interactions, Neurological Disorders, Molecular Biophysics and Computational Biology.

Figure 1. Overexpansion of trinucleotide repeat sequences forms an unusual (hairpin) nucleic acid structure; subsequently, either mismatch repair proteins (in DNA) or RNA-binding proteins (in RNA) sequester onto it. This leads to several neurological disorders, including Huntington's disease (CAG repeats), myotonic dystrophy type 1 (CUG repeats), several spinocerebellar ataxias (CAG repeats), etc.

Figure 2. Insights on the molecular mechanism of the transcription factor (TF): DNA regulation of the FKH domain in FoxP1. Schematics of the known mechanism by which TFs perform their function (unidirectional in black arrows), showing in red arrows the unknown molecular processes that must occur to turn off the function and disassemble the transcription complex. B) Domain organization of human FoxP proteins. (C) Three-dimensional structure of the monomer and 3D-DS dimer of FoxP1, indicating the different TF:DNA complexes. (D) smMFS allows us to determine the structural dynamics of the FKH domain in its monomeric and dimeric forms and when interacting with DNA. (Kolimi N. et al., Cell Rep. Phy. Sci., 2024)

Figure 3. Outline of the molecular dynamics simulation set-up for DNA duplex.

Figure 4. Single-molecule fluorescence anisotropy data registration and processing (Kolimi N., et al., JOVE, 2025).

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