Paul Robustelli

Dartmouth College

Hosted by: Vincenzo Venditti

**BioPhysical Seminar**

Targeting Intrinsically Disordered Proteins and Biomolecular Condensates with Small Molecule Drugs

Abstract:

Intrinsically disordered proteins (IDPs), which represent ~40% of the human proteome, play crucial roles in a variety of biological pathways and biomolecular assemblies and have been implicated in many human diseases. IDPs do not fold into a well-defined three-dimensional structure under physiological conditions. Instead, they populate a dynamic conformational ensemble of rapidly interconverting structures. As a result, IDPs are extremely difficult to experimentally characterize and are largely considered “undruggable” by conventional structure-based drug design methods.  Our laboratory utilizes a combination of computational and biophysical methods to characterize the molecular recognition mechanisms of intrinsically disordered proteins in atomic detail.  Here I will discuss recent progress in our efforts to characterize the interactions of IDPs with small molecule drugs, understand molecular mechanisms that drive the formation of biomolecular condensate, and understand how small molecule drugs modulate biomolecular condensate stability. 

Bio:

Paul Robustelli, PhD. is an assistant professor of chemistry at Dartmouth College, where his research focuses on the integration of computational and experimental methods to study dynamic and disordered proteins. Dr. Robustelli utilizes computer simulations and nuclear magnetic resonance (NMR) spectroscopy to model the conformational ensembles of intrinsically disordered proteins at atomic resolution to understand how small molecule drugs bind and inhibit disordered proteins and rationally design novel disordered protein inhibitors. Dr. Robustelli has made contributions to the development of physical models (“force fields”) that enable accurate simulations of disordered proteins and computational methods to integrate NMR data as restraints in molecular simulations.

Dr. Robustelli earned his B.A. in chemistry from Pomona College and his Ph.D. in chemistry from the University of Cambridge in the laboratory of Michele Vendruscolo.  Before joining the chemistry faculty at Dartmouth, Paul worked as a postdoctoral fellow at Columbia University in the laboratory of Arthur Palmer III and as a scientist at D.E. Shaw Research.