TY - JOUR T1 - Discovery of a cryptic allosteric site in Ebola’s ‘undruggable’ VP35 protein using simulations and experiments JF - bioRxiv DO - 10.1101/2020.02.09.940510 SP - 2020.02.09.940510 AU - Matthew A. Cruz AU - Thomas E. Frederick AU - Sukrit Singh AU - Neha Vithani AU - Maxwell I. Zimmerman AU - Justin R. Porter AU - Katelyn E. Moeder AU - Gaya K. Amarasinghe AU - Gregory R. Bowman Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/02/10/2020.02.09.940510.abstract N2 - Many proteins are classified as ‘undruggable,’ especially those that engage in protein-protein and protein-nucleic acid interactions. Discovering ‘cryptic’ pockets that are absent in available structures but open due to protein dynamics could provide new druggable sites. Here, we integrate atomically-detailed simulations and biophysical experiments to search for cryptic pockets in viral protein 35 (VP35) from the highly lethal Ebola virus. VP35 plays multiple essential roles in Ebola’s replication cycle, including binding the viral RNA genome to block a host’s innate immunity. However, VP35 has so far proved undruggable. Using adaptive sampling simulations and allosteric network detection algorithms, we uncover a cryptic pocket that is allosterically coupled to VP35’s key RNA-binding interface. Experimental tests corroborate the predicted pocket and confirm that stabilizing the open form allosterically disrupts RNA binding. These results demonstrate simulations’ power to characterize hidden conformations and dynamics, uncovering cryptic pockets and allostery that present new therapeutic opportunities. ER -