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Water regulates the residence time of Benzamidine in Trypsin

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  • Narjes Ansari

    (Italian Institute of Technology)

  • Valerio Rizzi

    (Italian Institute of Technology)

  • Michele Parrinello

    (Italian Institute of Technology)

Abstract

The process of ligand-protein unbinding is crucial in biophysics. Water is an essential part of any biological system and yet, many aspects of its role remain elusive. Here, we simulate with state-of-the-art enhanced sampling techniques the binding of Benzamidine to Trypsin which is a much studied and paradigmatic ligand-protein system. We use machine learning methods to determine efficient collective coordinates for the complex non-local network of water. These coordinates are used to perform On-the-fly Probability Enhanced Sampling simulations, which we adapt to calculate also the ligand residence time. Our results, both static and dynamic, are in good agreement with experiments. We find that the presence of a water molecule located at the bottom of the binding pocket allows via a network of hydrogen bonds the ligand to be released into the solution. On a finer scale, even when unbinding is allowed, another water molecule further modulates the exit time.

Suggested Citation

  • Narjes Ansari & Valerio Rizzi & Michele Parrinello, 2022. "Water regulates the residence time of Benzamidine in Trypsin," Nature Communications, Nature, vol. 13(1), pages 1-9, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33104-3
    DOI: 10.1038/s41467-022-33104-3
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    References listed on IDEAS

    as
    1. Nuria Plattner & Frank Noé, 2015. "Protein conformational plasticity and complex ligand-binding kinetics explored by atomistic simulations and Markov models," Nature Communications, Nature, vol. 6(1), pages 1-10, November.
    2. Steffen Wolf & Benjamin Lickert & Simon Bray & Gerhard Stock, 2020. "Multisecond ligand dissociation dynamics from atomistic simulations," Nature Communications, Nature, vol. 11(1), pages 1-8, December.
    3. Valerio Rizzi & Luigi Bonati & Narjes Ansari & Michele Parrinello, 2021. "The role of water in host-guest interaction," Nature Communications, Nature, vol. 12(1), pages 1-7, December.
    4. Johannes Schiebel & Roberto Gaspari & Tobias Wulsdorf & Khang Ngo & Christian Sohn & Tobias E. Schrader & Andrea Cavalli & Andreas Ostermann & Andreas Heine & Gerhard Klebe, 2018. "Intriguing role of water in protein-ligand binding studied by neutron crystallography on trypsin complexes," Nature Communications, Nature, vol. 9(1), pages 1-15, December.
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