Chasing the Full Free Energy Landscape of Neuroreceptor/Ligand Unbinding by Metadynamics Simulations

Journal article


Publication Details

Author(s): Capelli R, Bochicchio A, Piccini G, Casasnovas R, Carloni P, Parrinello M
Journal: Journal of Chemical Theory and Computation
Publication year: 2019
Volume: 15
Journal issue: 5
Pages range: 3354-3361
ISSN: 1549-9618
eISSN: 1549-9626


Abstract

Predicting the complete free energy landscape associated with protein-ligand unbinding may greatly help designing drugs with highly optimized pharmacokinetics. Here we investigate the unbinding of the iperoxo agonist to its target human neuroreceptor M
2
, 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.


FAU Authors / FAU Editors

Bochicchio, Anna
Professur für Computational Biology


External institutions with authors

Eidgenössische Technische Hochschule Zürich (ETHZ) / Swiss Federal Institute of Technology in Zurich
Forschungszentrum Jülich GmbH (FZJ)


How to cite

APA:
Capelli, R., Bochicchio, A., Piccini, G., Casasnovas, R., Carloni, P., & Parrinello, M. (2019). Chasing the Full Free Energy Landscape of Neuroreceptor/Ligand Unbinding by Metadynamics Simulations. Journal of Chemical Theory and Computation, 15(5), 3354-3361. https://dx.doi.org/10.1021/acs.jctc.9b00118

MLA:
Capelli, Riccardo, et al. "Chasing the Full Free Energy Landscape of Neuroreceptor/Ligand Unbinding by Metadynamics Simulations." Journal of Chemical Theory and Computation 15.5 (2019): 3354-3361.

BibTeX: 

Last updated on 2019-03-06 at 09:08