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.

Chasing the full free energy landscape of neuroreceptor/ligand unbinding by metadynamics simulations / R. Capelli, A. Bochicchio, G. Piccini, R. Casasnovas, P. Carloni, M. Parrinello. - In: JOURNAL OF CHEMICAL THEORY AND COMPUTATION. - ISSN 1549-9618. - 15:5(2019 May), pp. 3354-3361. [10.1021/acs.jctc.9b00118]

Chasing the full free energy landscape of neuroreceptor/ligand unbinding by metadynamics simulations

R. Capelli
Primo
;
2019

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.
Settore FIS/07 - Fisica Applicata(Beni Culturali, Ambientali, Biol.e Medicin)
Settore CHIM/02 - Chimica Fisica
Settore BIO/10 - Biochimica
   Human Brain Project Specific Grant Agreement 2 (HBP SGA2)
   HBP SGA2
   EUROPEAN COMMISSION
   H2020
   785907
mag-2019
Article (author)
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/933809
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