RT Journal Article
SR Electronic
T1 Chasing the full free energy landscape of neuroreceptor/ligand unbinding by metadynamics simulations
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 544577
DO 10.1101/544577
A1 Riccardo Capelli
A1 Anna Bochicchio
A1 GiovanniMaria Piccini
A1 Rodrigo Casasnovas
A1 Paolo Carloni
A1 Michele Parrinello
YR 2019
UL http://biorxiv.org/content/early/2019/02/08/544577.abstract
AB Predicting the complete free energy landscape associated with protein-ligand un-binding would greatly help designing drugs with highly optimized pharmacokinetics. Here we investigate the unbinding of the iperoxo agonist to its target human neuroreceptor M2, embedded in a neuronal membrane. By feeding out-of-equilibrium molecular simulations data in a classification analysis, we identify the few essential reaction coordinates of the process. The full landscape is then reconstructed using an exact enhanced sampling method, well-tempered metadynamics in its funnel variant. The calculations reproduce well the measured affinity, provide a rationale for mutagenesis data and show that the ligand can escape via two different routes. The allosteric modulator LY2119620 turns out to hamper both escapes routes, thus slowing down the unbinding process, as experimentally observed. This computationally affordable protocol is totally general and it can be easily applied to determine the full free energy landscape of membrane receptors/drug interactions.Graphical TOC Entry