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000866015 1001_ $$0P:(DE-Juel1)174546$$aCapelli, Riccardo$$b0$$eCorresponding author
000866015 245__ $$aChasing the Full Free Energy Landscape of Neuroreceptor/Ligand Unbinding by Metadynamics Simulations
000866015 260__ $$aWashington, DC$$c2019
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000866015 520__ $$aPredicting 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 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.
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000866015 7001_ $$0P:(DE-Juel1)169975$$aBochicchio, Anna$$b1
000866015 7001_ $$00000-0002-3511-4281$$aPiccini, GiovanniMaria$$b2
000866015 7001_ $$0P:(DE-HGF)0$$aCasasnovas, Rodrigo$$b3
000866015 7001_ $$0P:(DE-Juel1)145614$$aCarloni, Paolo$$b4$$eCorresponding author
000866015 7001_ $$0P:(DE-HGF)0$$aParrinello, Michele$$b5
000866015 773__ $$0PERI:(DE-600)2166976-4$$a10.1021/acs.jctc.9b00118$$gVol. 15, no. 5, p. 3354 - 3361$$n5$$p3354 - 3361$$tJournal of chemical theory and computation$$v15$$x1549-9626$$y2019
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000866015 8564_ $$uhttps://juser.fz-juelich.de/record/866015/files/muscarinic.pdf$$yPublished on 2019-03-26. Available in OpenAccess from 2020-03-26.
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000866015 8564_ $$uhttps://juser.fz-juelich.de/record/866015/files/muscarinic.pdf?subformat=pdfa$$xpdfa$$yPublished on 2019-03-26. Available in OpenAccess from 2020-03-26.
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