Our research is focused on four topics: the molecular basis of neurodegeneration in Huntington’s disease (HD) and related disorders, phase transitions that lead to protein and RNA condensates driven by multivalent molecules, the biophysics of intrinsically disordered proteins, and design of responsive, protein-based biomaterials. Our work is driven by a blend of multiscale computer simulations, adaptations and developments of polymer physics theories, new ideas regarding the physics of living systems, in vitro and in cell experiments, and collaborations that enable molecular and cellular level investigations.
Intrinsically disordered proteins (IDPs): These proteins are abundant in eukaryotic proteomes and are implicated in important cellular functions that underlie transcriptional regulation and signal transduction. We have developed and used novel combinations of polymer physics theories, molecular simulations, and biophysical experiments to provide definitive descriptors for the relationships between information encoded in IDP sequences and their conformational properties. We are using de novo sequence design to modulate conformational properties of IDPs and quantify the impact of these changes on functions of specific IDPs and the distinct cellular processes they control.
Neurodegeneration: We work on connecting the driving forces for and the mechanisms of polyglutamine aggregation and phase separation to intracellular interactions that lead to neurodegeneration in HD and other polyglutamine expansion disorders. An emerging focus is on the modulation of aggregation and phase behavior by endogeneous networks of protein-protein interactions.
Phase transitions and intracellular compartmentalization: We have considerable interest in the problem of phase transitions that are controlled or influenced by multivalent proteins and RNA molecules. These phase transitions include phase separation, sol-gel transitions, the formation of liquid crystals, and the design of novel, stimulus responsive biomaterials. We are developing multiscale, multiresolution methods to understand the driving forces for, mechanisms of, and functions associated with membraneless organelles, also known as biomolecular condensates, that form as the result of phase transitions. This problem has direct relevance to spatiotemporal organization and information transduction within cells.
Molecular Engineering: We are building on our work pertaining to phase transitions and IDPs to develop, prototype, and deploy computational methods to predict phase behavior from amino acid sequence and advance the design of responsive peptide and protein-based biomaterials.