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- A nd/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.

Accuracy of Molecular Simulation-Based Predictions of koff Values: A Metadynamics Study / R. Capelli, W. Lyu, V. Bolnykh, S. Meloni, J.M.H. Olsen, U. Rothlisberger, M. Parrinello, P. Carloni. - In: THE JOURNAL OF PHYSICAL CHEMISTRY LETTERS. - ISSN 1948-7185. - 11:15(2020), pp. 6373-6381. [10.1021/acs.jpclett.0c00999]

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

R. Capelli
Primo
;
2020

Abstract

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- A nd/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.
Chlorides; Density Functional Theory; Entropy; Isoxazoles; Ligands; Molecular Dynamics Simulation; Protein Conformation; Quaternary Ammonium Compounds; Receptors, Muscarinic; Sodium; Solvents; Static Electricity; Water
Settore FIS/07 - Fisica Applicata(Beni Culturali, Ambientali, Biol.e Medicin)
Settore CHIM/02 - Chimica Fisica
Settore BIO/10 - Biochimica
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/933818
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