Computational and biophysical approaches to disordered proteins

When Rohit Pappu was a postdoctoral fellow at Johns Hopkins University working on protein folding, he had a conversation with Keith Dunker, a pioneer in the field of intrinsically disordered proteins, or IDPs. Dunker then shared a paper with him.

“I read that through the night,” Pappu said.

Rohit Pappu

He realized that there might be a different way to think about IDPs — not just from a sequence analysis perspective, but also from a biophysical point of view.

After he set up his own lab at Washington University in St. Louis, Pappu started working on IDPs by combining atomistic and coarse-grained simulations with polymer physics principles to develop models that quantitatively describe their sequence–ensemble relationships.

The work in his lab has led to development of computational engines such as CAMPARI, LaSSI and CIDER. These are used to generate insights regarding the conformational ensembles, (CAMPARI), phase behaviors (LaSSI) and compositional biases as well as non-random sequence features of IDPs (CIDER). Insights and results from biophysical and informatics computations enable quantitative predictions that are testable using experiments, making these tools useful for the IDP and phase separation community and for noncomputational scientists.

Over the past two decades, Pappu’s work has been at the cornerstone of understanding function and phase behaviors of IDPs, and he will receive the American Society for Biochemistry and Molecular Biology’s 2025 DeLano Award for Computational Biosciences. Tanja Mittag and Alex Holehouse nominated Pappu for the award.

“The generality of conclusions borne from LaSSI simulations is a testament to the creativity of Prof. Pappu’s research program,” Mittag and Holehouse wrote in their nomination letter. “(T)he conceptual and computational ecosystem Prof. Pappu has developed over the course of his career has had a profound impact on the field of IDPs and biological phase separation.”