Journal
JOURNAL OF PHYSICAL CHEMISTRY LETTERS
Volume 11, Issue 15, Pages 6373-6381Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jpclett.0c00999
Keywords
-
Categories
Funding
- VSR on the supercomputer JURECA65 at Forschungszentrum Julich [jias5d]
- European Union [785907]
- Marie Sklodowska-Curie Grant [642069]
- Research Council of Norway through its Centres of Excellence scheme [262695]
- Swiss National Science Foundation via the NCCR MUST and individual grants
- Marie Curie Actions (MSCA) [642069] Funding Source: Marie Curie Actions (MSCA)
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available