Research Projects

Central dogma of molecular biology has experienced a shift from “information flow through DNA-RNA-protein sequences” toward a complex yet revealing mesh of protein-polynucleotides named biomolecular condensates and feedback loops. Condensates often act in cellular media as a catalytic container or even introduces time-dependent tunability of certain biological regulations by scavenging molecules like mRNA, different DNA and RNA binding proteins. Moreover, RNAs and proteins are almost every time in a state where multiple modification occur upon building blocks of the same in sequence specific manner and often interact with IDPs and even with post-translationally modified IDRs when mRNA is captured in a biomolecular condensate for sufficient time. Such context-dependent switches often tune the nature of biomolecular condensates efficiently in a dynamic non-equilibrium manner and still unknown. Even it is still a mystery how sequence-specific modifications alter conformational landscape of proteins and RNAs in a time-dependent manner and in turn can significantly tune the structure-stability-dynamics in heterotypic mesh as a function of time. Hence, our primary aim is to decode the alteration of single-molecule conformational landscape of proteins and RNAs upon introducing systematic sequence-specific and context dependent post-translational and post-transcriptional modifications and to unravel the thermodynamic and kinetic aspects of transitions among conformational states with all-atom explicit water simulations. In a complex interacting mesh, we hypothesize multiple reversible context-dependent modifications of RNA and proteins play a time-dependent key-role of a switch in tuning competing or synergistic interactions among IDR-RNA, RNA-RNA and IDR-IDR ones that significantly dictate stability, local heterogeneity in structure, dynamics and even multiphase creation and to be probed through an aptly calibrated coarse-grained structure-based model from our single-molecular understanding from all-atom simulations. 1. Our Proposed study will shed light into the effect of various time-dependent reversible post-translational and post-transcriptional modifications on the structural ensemble of disordered proteins and RNAs respectively at diverse functional contexts. 2. Our approaches will unravel insights into the tunability of molecular recognition mechanism and selectivity of one molecule over another one through different compositional control of such PTMs/PRMs in proteins and RNA. 3. Impact of the extent of mixing different PRMs/PTMs on condensate stability and its intrinsic dynamics will be elucidated.. 4. Finally, employing the knowledge gained we will classify combinatoric modifications as fatal or healthy and specific combinations may alter solid-like maturation of condensates in targeting fatal neurodegenerative diseases and reverse them to liquid-like ones with tuneable scavenging activity that can alter defective biological regulations.