TY  - JOUR
AU  - Capelli, Riccardo
AU  - Lyu, Wenping
AU  - Bolnykh, Viacheslav
AU  - Meloni, Simone
AU  - Olsen, Jógvan Magnus Haugaard
AU  - Rothlisberger, Ursula
AU  - Parrinello, Michele
AU  - Carloni, Paolo
TI  - Accuracy of Molecular Simulation-Based Predictions of k off Values: A Metadynamics Study
JO  - The journal of physical chemistry letters
VL  - 11
IS  - 15
SN  - 1948-7185
CY  - Washington, DC
PB  - ACS
M1  - FZJ-2020-03081
SP  - 6373 - 6381
PY  - 2020
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:32672983
UR  - <Go to ISI:>//WOS:000562064500081
DO  - DOI:10.1021/acs.jpclett.0c00999
UR  - https://juser.fz-juelich.de/record/884080
ER  -