Understanding Post-translational modifications

Protein post-translational modification (PTM) is among the key phenomena for regulating the activity of proteins as well as their diverse structures and functions. Phosphorylation, introducing a charged, anionic/di-anionic tetrahedral phosphate group on the Ser/Thr/Tyr side chain induces altered conformations in protein microenvironments, primarily due to the formation of salt bridges. Another PTM analogous to protein phosphorylation is O-Glycosylation, which also targets the alcoholic side chains of Ser/Thr/Tyr. The addition of β-linked N-acetylglucosamine (O-GlcNAc) is the only PTM that is observed within the nucleocytoplasmic compartments. O-GlcNAcylation and phosphorylation are involved in a complex interplay involving cell-signaling pathways, protein transcription, and cytoskeletal regulatory protein activity. 

The microtubule-associated protein Tau is a phosphoprotein in neurons of the brain. Aggregation of Tau is the leading cause of tauopathies such as Alzheimer’s disease. Tau undergoes several post-translational modifications of which phosphorylation and O-GlcNAcylation are key chemical modifications. Tau aggregates into paired helical filaments and neurofibrillary tangles upon hyperphosphorylation, whereas O-GlcNAcylation stabilizes the soluble form of Tau. How specific phosphorylation and/or O-GlcNAcylation events influence Tau conformations remains largely unknown due to the disordered nature of Tau. We have used a wide variety of computational simulations to understand the competitive influence of phosphorylation and O-GlcNAcylation on the structural propensities of the underlying protein with specific applications to Tau. 

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Conformational Dynamics of Carbohydrates

Carbohydrates are ubiquitous in nature and an integral component of biological systems. Besides their commonly known functions, such as energy storage and formation of structural components of cells, carbohydrates either alone or in conjunction with other biomolecules, such as proteins and lipids, mediate a wide range of cellular processes, from signal transduction, inflammation, viral replication, and immune response to protein stabilization and cryoprotection. They have also found applications in biotechnology in biocompatible and biodegradable materials and biofuels.

We are involved in both the development of the CHARMM carbohydrate force field and studying the conformational dynamics of carbohydrates. 

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Bio-Nanotechnology

Our interest is in studying the dynamics of biomolecules at interfaces. To this end, we are exploring the graphene sheet and associated 2D sheets as lead candidates for bio-molecular assembly. We have recently reported the development of Drude parameters for describing the polarizable graphene sheet compatible with the CHARMM Polarizable Force Field. We intend to study the influence of polarization on the self-assembly and nanopore characteristics of graphene. We are also developing parameters to describe h-BN and B-sheets.

We have shown that the polarizable graphene parameters capture the ion-graphene interactions and differentiate the ions based on their sizes and charges. This opens up the opportunity to study the ion-sieving behavior of graphene sheets.

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Article selected in 2023 Popular Advances collection Nanoscale Advances Popular Advances Collection 2023.

Force Field Development

Our group is actively contributing to the development of the CHARMM (Chemistry at Harvard Molecular Mechanics) force field. We have contributed to both the additive as well as polarizable force fields. 

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CHARMM Additive force field:


CHARMM Polarizable force field: