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Computational Biophysics & Structural Biology

 

The Robustelli group develops and applies computational methods to obtain atomic-level descriptions of the functional motions of biomolecules, with a particular interest in intrinsically disordered proteins. 

Intrinsically disordered proteins do not fold into well-defined tertiary structures under physiological conditions, but rather populate a heterogeneous conformational ensemble of rapidly interconverting structures.  These proteins are abundant in eukaryotic proteomes, play important functional roles in a large number cellular pathways and biomolecular assemblies, and have been implicated in a large number of human diseases. Due to their highly dynamic nature and conformational variability, disordered proteins have proven difficult to experimentally characterize at an atomic level and are not suitable targets for conventional structure-based drug design methods, in which small molecules are designed to optimize interactions with well-defined binding pockets. 

Our group utilizes molecular simulations to obtain atomistic descriptions of the molecular recognition mechanisms of intrinsically disordered proteins.  We aim to use insights form these simulations to understand, predict and ultimately design dynamic and heterogeneous binding interactions of disordered proteins.  The computational methods of our group are tightly integrated with biophysical experiments, particularly from NMR spectroscopy.  We utilize experimental data to develop new underlying physical models for our simulations and we directly incorporate information from experimental data into our simulations when existing physical models are insufficiently accurate. 

A current focus of our laboratory is understanding the thermodynamic driving forces of small molecule ligands binding to disordered protein sequences.  We hope that our research will help contribute to a general understanding of the principles of molecular recognition in intrinsically disordered proteins, stimulate the development of new paradigms that account for conformational disorder in small molecule binding and ultimately provide new avenues to therapeutic interventions in diseases associated with disordered protein dysfunction through the rational design of biologic and small molecule inhibitors.