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Accuracy of Molecular Simulation-Based Predictions of koff Values: A Metadynamics Study.
Journal article

Accuracy of Molecular Simulation-Based Predictions of koff Values: A Metadynamics Study.

  • Capelli R Computational Biomedicine Section, IAS-5/INM-9, Forschungzentrum Jülich, Wilhelm-Johnen-straße, D-52425 Jülich, Germany.
  • Lyu W Computational Biomedicine Section, IAS-5/INM-9, Forschungzentrum Jülich, Wilhelm-Johnen-straße, D-52425 Jülich, Germany.
  • Bolnykh V Computational Biomedicine Section, IAS-5/INM-9, Forschungzentrum Jülich, Wilhelm-Johnen-straße, D-52425 Jülich, Germany.
  • Meloni S Dipartimento di Scienze Chimiche e Farmaceutiche, Università degli Studi di Ferrara, Via Luigi Borsari 46, I-44121, Ferrara, Italy.
  • Olsen JMH Hylleraas Centre for Quantum Molecular Sciences, Department of Chemistry, UiT The Arctic University of Norway, N-9037 Tromsø, Norway.
  • Rothlisberger U Laboratory of Computational Chemistry and Biochemistry, École Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
  • Parrinello M Department of Chemistry and Applied Biosciences, ETH Zürich, c/o USI Campus, Via Giuseppe Buffi 13, CH-6900 Lugano, Ticino, Switzerland.
  • Carloni P Computational Biomedicine Section, IAS-5/INM-9, Forschungzentrum Jülich, Wilhelm-Johnen-straße, D-52425 Jülich, Germany.
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  • 2020-07-17
Published in:
  • The journal of physical chemistry letters. - 2020
General Materials Science
English The koff values of ligands unbinding to proteins are key parameters for drug discovery. Their predictions based on molecular simulation may under- or overestimate experiment in a system- and/or technique-dependent way. Here we use an established method-infrequent metadynamics, based on the AMBER force field-to compute the koff of the ligand iperoxo (in clinical use) targeting the muscarinic receptor M2. The ligand charges are calculated by either (i) the Amber standard procedure or (ii) B3LYP-DFT. The calculations using (i) turn out not to provide a reasonable estimation of the transition-state free energy. Those using (ii) differ from experiment by 2 orders of magnitude. On the basis of B3LYP DFT QM/MM simulations, we suggest that the observed discrepancy in (ii) arises, at least in part, from the lack of electronic polarization and/or charge transfer in biomolecular force fields. These issues might be present in other systems, such as DNA-protein complexes.
Language
  • English
Open access status
hybrid
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https://sonar.ch/global/documents/274870
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