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Small Glycols Discover Cryptic Pockets on Proteins for Fragment-based Approaches

Harsh Bansia, Pranjal Mahanta, Neela H Yennawar, Suryanarayanarao Ramakumar
doi: https://doi.org/10.1101/605121
Harsh Bansia
1Department of Physics, Indian Institute of Science, Bengaluru 560012, India
2Advanced Science Research Center at The Graduate Center of the City University of New York, New York, NY 10031, USA
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  • For correspondence: hbansia@gc.cuny.edu harsh@iisc.ac.in harsh3b@gmail.com
Pranjal Mahanta
1Department of Physics, Indian Institute of Science, Bengaluru 560012, India
3School of Biological Sciences, National Institute of Science Education and Research, Bhubaneswar 752050, India
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Neela H Yennawar
4The Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, PA 16802, USA
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Suryanarayanarao Ramakumar
1Department of Physics, Indian Institute of Science, Bengaluru 560012, India
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  • For correspondence: ramak@iisc.ac.in
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Abstract

Cryptic pockets are visible in ligand-bound protein structures but are occluded in unbound structures. Utilizing these pockets in fragment-based drug-design provides an attractive option for proteins not tractable by classical binding sites. However, owing to their hidden nature, they are difficult to identify. Here, we show that small glycols find cryptic pockets on diverse set of proteins. Initial crystallography experiments serendipitously revealed the ability of ethylene glycol, a small glycol, to identify a cryptic pocket on W6A mutant of RBSX protein (RBSX-W6A). Explicit-solvent molecular dynamics (MD) simulations of RBSX-W6A with exposed-state of the cryptic pocket (ethylene glycol removed) revealed closure of the pocket reiterating that cryptic pockets in general prefer to stay in closed-state in absence of the ligands. Also, no change in the pocket was observed for simulations of RBSX-W6A with occluded-state of the cryptic pocket, suggesting that water molecules are not able to open the cryptic pocket. “Cryptic-pocket finding” potential of small glycols was then supported and generalized through additional crystallography experiments, explicit-cosolvent MD simulations, protein dataset construction and analysis. The cryptic pocket on RBSX-W6A was found again upon repeating the crystallography experiments with another small glycol, propylene glycol. Use of ethylene glycol as probe molecule in cosolvent MD simulations led to the enhanced sampling of the exposed-state of experimentally observed cryptic sites on test set of two proteins (Niemann-Pick C2, Interleukin-2). Further, analyses of protein structures with validated cryptic sites showed that ethylene glycol molecules binds to sites on proteins (G-actin, Myosin II, Bcl-xL, Glutamate receptor 2) which become apparent upon binding of biologically relevant ligands. Our study thus suggests potential application of the small glycols in experimental and computational fragment-based approaches to identify cryptic pockets in apparently undruggable and/or difficult targets, making these proteins amenable to drug-design strategies.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • Databases: The atomic coordinates and structure factors of all the three structures have been deposited by us in Protein Data Bank (PDB) and are available under the accession codes 5EFD, 5XC0 and 5XC1.

  • Conflicts of interest: There are no conflicts of interest to declare.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted August 23, 2020.
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Small Glycols Discover Cryptic Pockets on Proteins for Fragment-based Approaches
Harsh Bansia, Pranjal Mahanta, Neela H Yennawar, Suryanarayanarao Ramakumar
bioRxiv 605121; doi: https://doi.org/10.1101/605121
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Small Glycols Discover Cryptic Pockets on Proteins for Fragment-based Approaches
Harsh Bansia, Pranjal Mahanta, Neela H Yennawar, Suryanarayanarao Ramakumar
bioRxiv 605121; doi: https://doi.org/10.1101/605121

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