Accuracy of Molecular Simulation-Based Predictions of k(off) Values: A Metadynamics Study

The k(off) 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 k(off )of the ligand iperoxo (in clinical use) targeting the muscarinic receptor M-2. 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.


Published in:
Journal Of Physical Chemistry Letters, 11, 15, 6373-6381
Year:
Aug 06 2020
Publisher:
Washington, AMER CHEMICAL SOC
ISSN:
1948-7185
Keywords:
Laboratories:




 Record created 2020-09-06, last modified 2020-09-11


Rate this document:

Rate this document:
1
2
3
 
(Not yet reviewed)