A General Mechanism for Signal Propagation in the Nicotinic Acetylcholine Receptor Family

Ana Sofia F. Oliveira, Christopher J Edsall, Christopher J Woods, Phil Bates, Gerardo Viedma Nunez, Susan Wonnacott, Isabel Bermudez, Giovanni Ciccotti, Timothy Gallagher, Richard B Sessions, Adrian J Mulholland

Research output: Contribution to journalArticle (Academic Journal)peer-review

17 Citations (Scopus)
154 Downloads (Pure)


Nicotinic acetylcholine receptors (nAChRs) modulate synaptic activity in the central nervous system. The α7 subtype, in particular, has attracted considerable interest in drug discovery as a target for several conditions, including Alzheimer's disease and schizophrenia. Identifying agonist-induced structural changes underlying nAChR activation is fundamentally important for understanding biological function and rational drug design. Here, extensive equilibrium and nonequilibrium molecular dynamics simulations, enabled by cloud-based high-performance computing, reveal the molecular mechanism by which structural changes induced by agonist unbinding are transmitted within the human α7 nAChR. The simulations reveal the sequence of coupled structural changes involved in driving conformational change responsible for biological function. Comparison with simulations of the α4β2 nAChR subtype identifies features of the dynamical architecture common to both receptors, suggesting a general structural mechanism for signal propagation in this important family of receptors.

Original languageEnglish
Article number51
Pages (from-to)19953-19958
Number of pages6
JournalJournal of the American Chemical Society
Issue number51
Early online date6 Dec 2019
Publication statusPublished - 26 Dec 2019


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