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Instruments / Technical Area	Publication Details	Published	Actions
I04-1-Macromolecular Crystallography (fixed wavelength) I04-Macromolecular Crystallography	Benzene Probes in Molecular Dynamics Simulations Reveal Novel Binding Sites for Ligand Design Yaw Sing Tan , Judith Reeks , Christopher J. Brown , Dawn Thean , Fernando Jose Ferrer Gago , Tsz Ying Yuen , Eunice Tze Leng Goh , Xue Er Cheryl Lee , Claire E. Jennings , Thomas L. Joseph , Rajamani Lakshminarayanan , David P. Lane , Martin E. M. Noble , Chandra S. Verma The Journal Of Physical Chemistry Letters 7, 3452 - 3457 DOI: 10.1021/acs.jpclett.6b01525 Diamond Proposal Number(s): [9948] Show Abstract ▼ Abstract: Protein flexibility poses a major challenge in binding site identification. Several computational pocket detection methods that utilize small-molecule probes in molecular dynamics (MD) simulations have been developed to address this issue. Although they have proven hugely successful at reproducing experimental structural data, their ability to predict new binding sites that are yet to be identified and characterized has not been demonstrated. Here, we report the use of benzenes as probe molecules in ligand-mapping MD (LMMD) simulations to predict the existence of two novel binding sites on the surface of the oncoprotein MDM2. One of them was serendipitously confirmed by biophysical assays and X-ray crystallography to be important for the binding of a new family of hydrocarbon stapled peptides that were specifically designed to target the other putative site. These results highlight the predictive power of LMMD and suggest that predictions derived from LMMD simulations can serve as a reliable basis for the identification of novel ligand binding sites in structure-based drug design.	Sep 2016

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I04-1-Macromolecular Crystallography (fixed wavelength)
I04-Macromolecular Crystallography

Benzene Probes in Molecular Dynamics Simulations Reveal Novel Binding Sites for Ligand Design