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.
Relevant Publications
Phosphorylation-Induced Structural Reorganization in Tau-Paired Helical Filaments; Lata Rani and Sairam S. Mallajosyula; ACS Chemical Neuroscience 2021, 12 (9), 1621-1631.
Effect of Phosphorylation and O-GlcNAcylation on Proline-Rich Domains of Tau; Lata Rani, Jeetain Mittal and Sairam S. Mallajosyula; J. Phys. Chem. B 2020, 124, 10, 1909–1918
Phosphorylation versus O-GlcNAcylation: Computational Insights into the Differential Influences of the Two Competitive Post-Translational Modifications; Lata Rani and Sairam S. Mallajosyula; J. Phys. Chem. B 2017, 121, 47, 10618–10638
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.
Relevant Publications
Impact of Polarization on the Ring Puckering Dynamics of Hexose Monosaccharides; J. N. Chythra and Sairam S. Mallajosyula, J. Chem. Inf. Model. 2023, 63, 208-223
Elucidating the role of key structural motifs in antifreeze glycoproteins; Poonam Pandey and Sairam S. Mallajosyula; Phys. Chem. Chem. Phys., 2019, 21, 3903-3917
Influence of Polarization on Carbohydrate Hydration: A Comparative Study Using Additive and Polarizable Force Fields; Poonam Pandey and Sairam S. Mallajosyula; J. Phys. Chem. B 2016, 120, 27, 6621–6633
Perturbation of long-range water dynamics as the mechanism for the antifreeze activity of antifreeze glycoprotein; Sairam S. Mallajosyula, Kenno Vanommeslaeghe, Alexander D. MacKerell Jr.,J. Phys. Chem. B 2014, 118, 11696-706.
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.
Relevant Publications
Graphene: From Solid Support for Nucleobase Assisted Self- Assemblies to Functional Material for DNA Sequencing, Hemanth Haridas and Sairam S. Mallajosyula, Journal of Physical Chemistry C 2024, 128, 3091-3112.
Unveiling DNA Translocation in Pristine Graphene Nanopores: Understanding Pore Clogging via Polarizable Simulations, Hemanth Haridas and Sairam S. Mallajosyula, ACS Applied Materials & Interfaces 2023, 15 (47), 55095-55108.
Capturing Charge and Size Effects of Ions at the Graphene- Electrolyte Interface Using Polarizable Force Field Simulations, Hemanth Haridas, Rohan Mewada and Sairam S. Mallajosyula, Nanoscale Advances 2023, 5, 796-804.
Article selected in 2023 Popular Advances collection Nanoscale Advances Popular Advances Collection 2023.
Capturing Concentration-Induced Aggregation of Nucleobases on a Graphene Surface through Polarizable Force Field Simulations, Hemanth Haridas, Pradeep Kumar Yadav and Sairam S. Mallajosyula, The Journal of Physical Chemistry C 2022, 126 (31), 13122-13131.
Polarization influences the evolution of nucleobase–graphene interactions, Hemanth Haridas and Sairam S. Mallajosyula; Nanoscale 2021, 13, 4060-4072.
Adsorption of DNA Bases on Two-Dimensional Boron Sheets, Amita Sihag and Sairam S. Mallajosyula; Chemistry Select 2019, 4, 3308-3314.
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.
Relevant Publications
CHARMM Additive force field:
CHARMM Additive All-Atom Force Field for Carbohydrate Derivatives and Its Utility in Polysaccharide and Carbohydrate–Protein Modeling; Olgun Guvench, Sairam S. Mallajosyula, E. Prabhu Raman, Elizabeth Hatcher, Kenno Vanommeslaeghe, Theresa J. Foster, Francis W. Jamison, II, and Alexander D. MacKerell, Jr.; J. Chem. Theory Comput. 2011, 7, 10, 3162–3180
CHARMM Additive All-Atom Force Field for Phosphate and Sulfate Linked to Carbohydrates; Sairam S. Mallajosyula, Olgun Guvench, Elizabeth Hatcher, and Alexander D. MacKerell, Jr.; J. Chem. Theory Comput. 2012, 8, 2, 759–776
CHARMM Polarizable force field:
Impact of Polarization on the Ring Puckering Dynamics of Hexose Monosaccharides J. N. Chythra and Sairam S. Mallajosyula; J. Chem. Inf. Model. 2023, 63, 208-223
Drude Polarizable Force Field Parametrization of Carboxylate and N-Acetyl Amine Carbohydrate Derivatives Poonam Pandey, Asaminew H. Aytenfisu, Alexander D. MacKerell Jr., and Sairam S. Mallajosyula; J. Chem. Theory Comput. 2019, 15, 9, 4982–5000
Polarization influences the evolution of nucleobase–graphene interactions Hemanth. H and Sairam S. Mallajosyula; Nanoscale, 2021, 13, 4060-4072