American Chemical Society
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PlayMolecule CrypticScout: Predicting Protein Cryptic Sites Using Mixed-Solvent Molecular Simulations

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journal contribution
posted on 2020-04-01, 18:33 authored by Gerard Martinez-Rosell, Silvia Lovera, Zara A. Sands, Gianni De Fabritiis
Cryptic pockets are protein cavities that remain hidden in resolved apo structures and generally require the presence of a co-crystallized ligand to become visible. Finding new cryptic pockets is crucial for structure-based drug discovery to identify new ways of modulating protein activity and thus expand the druggable space. We present here a new method and associated web application leveraging mixed-solvent molecular dynamics (MD) simulations using benzene as a hydrophobic probe to detect cryptic pockets. Our all-atom MD-based workflow was systematically tested on 18 different systems and 5 additional kinases and represents the largest validation study of this kind. CrypticScout identifies benzene probe binding hotspots on a protein surface by mapping probe occupancy, residence time, and the benzene occupancy reweighed by the residence time. The method is presented to the scientific community in a web application available via using a distributed computing infrastructure to perform the simulations.