This title appears in the Scientific Report :
2020
Please use the identifier:
http://dx.doi.org/10.1021/acs.jpclett.0c00999 in citations.
Please use the identifier: http://hdl.handle.net/2128/25667 in citations.
Accuracy of Molecular Simulation-Based Predictions of k off Values: A Metadynamics Study
Accuracy of Molecular Simulation-Based Predictions of k off Values: A Metadynamics Study
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 for...
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Personal Name(s): | Capelli, Riccardo (Corresponding author) |
---|---|
Lyu, Wenping / Bolnykh, Viacheslav / Meloni, Simone / Olsen, Jógvan Magnus Haugaard / Rothlisberger, Ursula / Parrinello, Michele / Carloni, Paolo | |
Contributing Institute: |
JARA - HPC; JARA-HPC Computational Biomedicine; INM-9 Computational Biomedicine; IAS-5 |
Published in: | The journal of physical chemistry letters, 11 (2020) 15, S. 6373 - 6381 |
Imprint: |
Washington, DC
ACS
2020
|
PubMed ID: |
32672983 |
DOI: |
10.1021/acs.jpclett.0c00999 |
Document Type: |
Journal Article |
Research Program: |
HPC-aided design of drugs with improved kinetics of binding Theory, modelling and simulation |
Link: |
Get full text Get full text Published on 2020-07-16. Available in OpenAccess from 2021-07-16. Published on 2020-07-16. Available in OpenAccess from 2021-07-16. |
Publikationsportal JuSER |
Please use the identifier: http://hdl.handle.net/2128/25667 in citations.
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. |