The koff values of ligands unbinding to proteins are key parameters for drug discovery. Their predictions based on molecular simulation may under- or overestimate experimental values in a system- and/or technique-dependent way. We discuss the unbinding process of muscarinic receptor M2 in complex with iperoxo, a radioligand routinely used in clinics. Our findings suggest that, despite a precise representation of the bound and solvated states using the AMBER force field, we have a dramatic error in energy evaluation of energetics at the transition state that leads to a large error in our estimation of koff (koffMetaD= 3.7±0.7×10–4 s–1, with an experimental value of koffexp=1.0±0.2×10–2 s–1). We investigated the polarization effects involved in the unbinding transition with QM/MM calculations at B3LYP level of theory, confirming that the lack of polarization in the classical representation of the system can be a key factor for this overestimation in residence time.

Accuracy of in silico kinetics calculations using infrequent metadynamics: The case of M2/iperoxo unbinding

ACS Spring Meeting 2021

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.