CUR - The Council on Undergraduate Research

Identification of Binding Hotspots on Med25

Authors: Anthony J. Dominic, Debarati DasGupta, Babak Mahjour, and Heather A. Carlson Faculty Mentor: Heather A. Carlson Institution: University of Michigan Institution Address: College of Pharmacy 428 Church Street Ann Arbor, MI 48109

Structure-based drug discovery relies on the identification of binding sites on protein surfaces. Mixed-solvent molecular dynamics (MixMD) is a technique used to identify druggable sites via simulation of an unbound protein in a 5% cosolvent and water solution. Water soluble cosolvents are used at low concentrations to allow for competition between cosolvent and water molecules at the surface of the protein. Sites mapped by at least two probes at a high signal-to-noise ratio is defined to be a hotspot or a potential binding site. Previous work has used MixMD to successfully identify competitive and allosteric sites on seven protein systems including: ABL Kinase, Androgen Receptor, CHK1 Kinase, Glucokinase, PDK1 Kinase, FPPS, and PTP1B. In this work, MixMD was used to identify two hotspots on the mediator Med25 activator interaction domain protein, a key component of the RNA polymerase type II complex in gene transcription. Docking experiments are underway to further assess the druggability of these identified sites. The molecular dynamics simulations at the heart of the MixMD method rely on integrating Newton’s equations of motion over time. The simulations are executed using the software AMBER18.

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