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You are here: Home Administration Chemistry & Biochemistry Department Events 2019 March Biochemistry Seminar: Paul Robustelli, "Improved Physical Models Enable the Investigation of Molecular Recognition in Intrinsically Disordered Proteins at Atomistic Resolution"

Biochemistry Seminar: Paul Robustelli, "Improved Physical Models Enable the Investigation of Molecular Recognition in Intrinsically Disordered Proteins at Atomistic Resolution"

Paul Robustelli, Research Fellow, Chemistry, Biology, and Drug Discovery Research Group, D.E. Shaw Research, NY, "Improved Physical Models Enable the Investigation of Molecular Recognition in Intrinsically Disordered Proteins at Atomistic Resolution"
When Mar 13, 2019
from 12:00 PM to 01:00 PM
Where CUNY ASRC Main Auditorium
Contact Name
Contact Phone 212-650-8803
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ABSTRACT

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 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.

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