TYC Lunchtime Seminar: Molecular Recognition Mechanisms of Intrinsically Disordered Proteins

Paul Robustelli, D.E. Shaw Research / Dartmouth College

Friday 6th December2019
Time: 1-2pm
Venue: Physics A1/3, followed by snacks and refreshments in A13 Tampa Common Room
Contact: Karen Stoneham
Tel: 0207 679 7306


Molecular dynamics (MD) simulation can serve as a valuable complementary tool to experiments in characterizing the structural and dynamic properties of intrinsically disordered proteins.    By comparing long-timescale simulations of ordered and disordered proteins to experimental data, we have systematically identified limitations in current physical models and have developed new force fields that provide substantially improved accuracy in simulations of disordered proteins while maintaining state-of-the-art accuracy for folded proteins.  These new force fields have enabled us to study mechanisms of molecular recognition in intrinsically disordered proteins in atomistic detail.  In unbiased MD simulations of an intrinsically disordered protein and its physiological binding partner, for example, we observe a large number of spontaneous folding-upon-binding events, allowing us to carefully dissect and characterize the observed binding mechanisms.  In a second application, unbiased MD simulations of the intrinsically disordered protein α-synuclein with a small molecule ligand reproduce a binding interaction observed by NMR spectroscopy experiments.  These simulations have enabled us to rationalize the molecule’s affinity for the experimentally observed binding site using a dynamic binding mechanism model in which α-synuclein remains flexible as it interacts with the small molecule in a variety of binding modes.  Based on this mechanism, we have conducted a computational screen of small molecules selected to modify the bound ensemble and the affinity of the interaction. NMR measurements of a representative series of small molecules are in line with predictions of relative binding affinities and have provided support for details of the simulated binding mechanism and its perturbations.  We are currently exploring the possibility of using dynamic binding mechanisms observed in MD simulations to rationally design molecules that exhibit improved binding to intrinsically disordered proteins.


Paul received Ph.D. in chemistry from the University of Cambridge in the laboratory of Prof. Michele Vendruscolo, where he worked on developing new techniques for determining the structure and conformational dynamics of proteins.   Paul then worked as an NSF Postdoctoral Research Fellow at Columbia University in the laboratory of Prof. Arthur G. Palmer III, where he studied the role of conformational dynamics in protein function with NMR spectroscopy and molecular simulations, and as a research scientist at D.E. Shaw Research, where he developed new physical models, or force fields, for MD simulations and applied these models to study molecular recognition mechanisms of intrinsically disordered proteins.  This January, Paul will be starting as an Assistant Professor of Chemistry at Dartmouth College.


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