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PhD Student, Indian Institute of Technology Kanpur


My work focus on protein aggregation involved in neurodegenetaive diseases.

I am a final year PhD student at the Indian Institute of Technology Kanpur, India with prior industrial experience on biotherapeutics at Biocon. My research focuses on understanding of mechanism behind protein aggregation linked to neurological disorders and development of potential therapeutics specifically for Huntington’s disease (HD). Compelling evidence indicates protein aggregation responsible for cellular abnormalities including disruption of degradation machineries, is one of the potential therapeutic target for HD and I have discovered two different classes of aggregation inhibitors and filed Indian patents for both (1182/DEL/2015 and 201611003335). We observed arginine based derivatives exhibited anti-aggregation effect against intrinsically disordered Htt polypeptides both in vitro and in HD model organisms (yeast and Drosophila). In order to understand structural basis of inhibition, we choose short peptide NT17 responsible for accelerating Htt aggregation. Now in order to get broad picture of shape and to probe the global changes in NT17 structure in presence of arginine based inhibitors, we intend to perform SAXS with our collaborator Dr. Ashish (IMTECH Chandigarh), so to understand mechanism behind aggregation inhibition and complement it with AUC and NMR spectroscopy data. SAXS will provide information of how at different concentrations of additive, it is undergoing structural changes from extended to globular or compact form. Integration of SAXS-NMR technique together will enable fragment based drug screening for intrinsically disordered peptide implicated in Huntington’s disease. Earlier, we performed SAXS experiment on understanding of one of inhibitor binding to albumin in solution.
We finally intend to have one lead molecule that we can be tested in preclinical setup.


Unmasking the roles of N- and C-terminal flanking sequences from exon 1 of huntingtin as modulators of polyglutamine aggregation.

Abstract: Huntington disease is caused by mutational expansion of the CAG trinucleotide within exon 1 of the huntingtin (Htt) gene. Exon 1 spanning N-terminal fragments (NTFs) of the Htt protein result from aberrant splicing of transcripts of mutant Htt. NTFs typically encompass a polyglutamine tract flanked by an N-terminal 17-residue amphipathic stretch (N17) and a C-terminal 38-residue proline-rich stretch (C38). We present results from in vitro biophysical studies that quantify the driving forces for and mechanisms of polyglutamine aggregation as modulated by N17 and C38. Although N17 is highly soluble by itself, it lowers the saturation concentration of soluble NTFs and increases the driving force, vis-à-vis homopolymeric polyglutamine, for forming insoluble aggregates. Kinetically, N17 accelerates fibril formation and destabilizes nonfibrillar intermediates. C38 is also highly soluble by itself, and it lends its high intrinsic solubility to lower the driving force for forming insoluble aggregates by increasing the saturation concentration of soluble NTFs. In NTFs with both modules, N17 and C38 act synergistically to destabilize nonfibrillar intermediates (N17 effect) and lower the driving force for forming insoluble aggregates (C38 effect). Morphological studies show that N17 and C38 promote the formation of ordered fibrils by NTFs. Homopolymeric polyglutamine forms a mixture of amorphous aggregates and fibrils, and its aggregation mechanisms involve early formation of heterogeneous distributions of nonfibrillar species. We propose that N17 and C38 act as gatekeepers that control the intrinsic heterogeneities of polyglutamine aggregation. This provides a biophysical explanation for the modulation of in vivo NTF toxicities by N17 and C38.

Pub.: 28 Nov '13, Pinned: 27 Jul '17

Molecular Mechanism on Stabilizing Huntingtin N17 Helical Structure in Micelle Environment.

Abstract: Huntington's disease is a deadly neurodegenerative disease caused by the fibrilization of huntingtin (HTT) exon-1 protein mutants. Despite extensive efforts over the past decade, much remains unknown about the structures of (mutant) HTT exon-1 and their enigmatic roles in aggregation. Particularly, whether the first 17 residues in the N-terminal (HTT-N17) adopt a helical or a coiled structure remains unclear. Here, with the rigorous study of molecular dynamics simulations, we explored the most possible structures of HTT-N17 in both dodecylphosphocholine (DPC) micelles and aqueous solution, using three commonly applied force fields (OPLS-AA/L, CHARMM36 and AMBER99sb*-ILDNP) to examine the underlying molecular mechanism and rule out the potential artifacts. We show that local environments are essential for determining the secondary structure of HTT-N17. This is evidenced by the insertion of five hydrophobic residues of HTT-N17 into the DPC micelle which promotes the formation of an amphipathic helix, while such amphipathic helix unfolds quickly in aqueous solution. A relatively low free energy barrier (~3 kcal/mol) for the secondary structure transformation was also observed for all three force fields from their respective folding free energy landscapes, which accounts for possible HTT-N17 conformational changes upon environment shifts such as membrane binding and protein complex aggregation.

Pub.: 18 Apr '17, Pinned: 27 Jul '17