Research in the Pappu lab is focused on intrinsically disordered proteomes. Multiscale modeling approaches and biophysical tools are used in this research. Eukaryotic proteomes are enriched in proteins that function despite being unable to fold autonomously into well defined three-dimensional structures. These intrinsically disordered proteins (IDPs) challenge the conventional wisdom regarding protein structure-function relationships and are involved in regulating signaling and transcription by serving as hubs in protein interaction networks. The lab is working on the sequence determinants of flavors of disorder to facilitate de novo design and remodeling of protein interaction networks. Studies are also focused on the mechanisms of IDP self-assembly that lead to the onset and progression of neurodegenerative disorders such as Alzheimer’s and Huntington’s disease.
In specific projects Pappu’s team has focused on the mechanisms of protein aggregation using a combination of polymer physics, multiscale simulations, as well as in vitro and in cell experiments. The current focus is on the mechanisms of aggregation of proteins with expanded polyglutamine tracts. This is directly relevant to Huntington’s disease and eight other neurodegenerative disorders. Recent efforts have focused on the cis-regulation of polyglutamine aggregation by flanking sequences derived from huntingtin and the interplay between aggregation and heterotypic interactions as determinants of neurodegeneration. 
Investigations of sequence-to-ensemble relationships of IDPs are being leveraged to understand how conformational heterogeneity is used to achieve specificity in molecular recognition. The systems of active investigation include dimer-forming transcription factors, single-stranded DNA binding proteins that are hubs in DNA metabolism and repair, the Notch intracellular domain that is central to determining cellular fate, proteins of the nuclear transport system, microtubule associated proteins that regulate axonal transport, and RNA binding proteins involved in bacterial anti-termination and regulation of splicing. Efforts are underway to extract common principles from the study of specific IDP systems in order to converge on a framework that enables the prediction and remodeling of cellular phenotypes that result from integrative responses of nested hierarchies of biomolecular networks.

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