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

Research output: Contribution to journalArticlepeer-review

Abstract

Proteinflexibility poses a major challenge in binding siteidentification. Several computational pocket detection methods thatutilize small-molecule probes in molecular dynamics (MD) simulationshave been developed to address this issue. Although they have provenhugely successful at reproducing experimental structural data, their abilityto predict new binding sites that are yet to be identified and characterizedhas not been demonstrated. Here, we report the use of benzenes as probemolecules in ligand-mapping MD (LMMD) simulations to predict theexistence of two novel binding sites on the surface of the oncoproteinMDM2. One of them was serendipitously confirmed by biophysicalassays and X-ray crystallography to be important for the binding of a newfamily of hydrocarbon stapled peptides that were specifically designed to target the other putative site. These results highlight thepredictive power of LMMD and suggest that predictions derived from LMMD simulations can serve as a reliable basis for theidentification of novel ligand binding sites in structure-based drug design
Original languageEnglish
Pages (from-to)3452-3457
Number of pages3457
JournalJournal of Physical Chemistry Letters
Volume7
DOIs
Publication statusPublished - 17 Aug 2016

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