Journal Article

FZJ-2020-03081

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Accuracy of Molecular Simulation-Based Predictions of k off Values: A Metadynamics Study

Capelli, R. (Corresponding author)FZJ* ; Lyu, W.FZJ* ; Bolnykh, V.FZJ* ; Meloni, S.Extern* ; Olsen, J. M. H.Extern* ; Rothlisberger, U.Extern* ; Parrinello, M.Extern* ; Carloni, P.FZJ*

2020
ACS Washington, DC

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Please use a persistent id in citations: http://hdl.handle.net/2128/25667  doi:10.1021/acs.jpclett.0c00999

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- 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.

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Contributing Institute(s):

1. Computational Biomedicine (IAS-5)
2. Computational Biomedicine (INM-9)
3. JARA - HPC (JARA-HPC)

Research Program(s):

1. 574 - Theory, modelling and simulation (POF3-574) (POF3-574)
2. HPC-aided design of drugs with improved kinetics of binding (jias5d_20181101) (jias5d_20181101)

Appears in the scientific report 2020

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Database coverage:
; ; Clarivate Analytics Master Journal List ; Current Contents - Physical, Chemical and Earth Sciences ; Essential Science Indicators ; IF >= 5 ; JCR ; NCBI Molecular Biology Database ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Web of Science Core Collection

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