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

Capelli R, Bochicchio A, Piccini G, Casasnovas R, Carloni P, Parrinello M (2019)

Publication Type: Journal article

Publication year: 2019

Journal

Journal of Chemical Theory and Computation American Chemical Society

Book Volume: 15

Pages Range: 3354-3361

Journal Issue: 5

DOI: 10.1021/acs.jctc.9b00118

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.

Authors with CRIS profile

Anna Bochicchio Professur für Computational Biology

Involved external institutions

Eidgenössische Technische Hochschule Zürich (ETHZ) / Swiss Federal Institute of Technology in Zurich CH Switzerland (CH) Forschungszentrum Jülich / Research Centre Jülich (FZJ) DE Germany (DE)

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.

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