On the accuracy of molecular simulation-based predictions of koffvalues: a Metadynamics study

Molecular simulations have made great progresses in predicting k off values—the kinetic constant of drug unbinding, a key parameter for modern pharmacology—yet computed values under- or over-estimate experimental data in a system- and/or technique-dependent way. In an effort at gaining insights on this issue, here we used an established method to calculate k off values—frequency-adaptive metadynamics with force field— and a subsequent QM/MM descriptions of the interactions. First, using force field-based metadynamics, we calculate k off of the Positron Emission Tomography (PET) ligand iperoxo targeting the human muscarinic acetylcholine receptor M 2 . In line with previously performed in silico studies, the prediction (3.7 ± 0.7 ⋅ 10 −4 s −1 ) turned out to differ significantly from the experimentally measured value (1.0 ± 0.2 ⋅ 10 −2 s −1 ). Next, we use DFT-based QM/MM simulations to show that this discrepancy arises from erroneous force field energetics at the transition state. It turns out that this discrepancy is partly caused by lack of electronic polarization and/or charge transfer in commonly employed force field. We expect these issues to arise also in other systems where charged portions of the system play a pivotal role, such as protein- or DNA-protein complexes. Graphical TOC Entry