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

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...

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Bibliographic Details
Published in:Journal of chemical information and modeling 2020-04, Vol.60 (4), p.2314-2324
Main Authors: Martinez-Rosell, Gerard, Lovera, Silvia, Sands, Zara A, De Fabritiis, Gianni
Format: Article
Language:English
Subjects:
Applications programs
Benzene
Binding Sites
Crystallization
Hydrocarbons
Hydrophobic and Hydrophilic Interactions
Kinases
Ligands
Mapping
Molecular dynamics
Molecular Dynamics Simulation
Occupancy
Proteins
Residence time distribution
Solvents
Workflow
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Summary: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 www.playmolecule.org using a distributed computing infrastructure to perform the simulations.
ISSN:1549-9596
1549-960X
DOI:10.1021/acs.jcim.9b01209