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

J Chem Inf Model. 2020 Apr 27;60(4):2314-2324. doi: 10.1021/acs.jcim.9b01209. Epub 2020 Apr 1.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Hydrophobic and Hydrophilic Interactions
  • Ligands
  • Molecular Dynamics Simulation*
  • Solvents*

Substances

  • Ligands
  • Solvents