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

doi:10.1021/jacs.9b09055

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

Department of Life Sciences

Research output: Contribution to journal › Article › peer-review

23 Citations (SciVal)

Abstract

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 language	English
Pages (from-to)	19953-19958
Number of pages	6
Journal	Journal of the American Chemical Society
Volume	141
Issue number	51
Early online date	6 Dec 2019
DOIs	https://doi.org/10.1021/jacs.9b09055
Publication status	Published - 26 Dec 2019

Funding

We thank EPSRC (EP/N024117/1, EP/N018591/1, and EP/M022609/1) for support. The equilibrium simulations were carried out using the computational facilities of the Advanced Computing Research Centre, University of Bristol ( http://www.bris.ac.uk/acrc ). All nonequilibrium simulations were performed in the Oracle Public Cloud Infrastructure ( https://cloud.oracle.com/en_US/iaas ). This work received generous support from the Oracle Cloud Innovation Accelerator ( https://www.oracle.com/industries/education-and-research/innovation-accelerator/ ) to enable data processing and molecular dynamics simulations using Oracle’s high-performance public cloud infrastructure ( https://cloud.oracle.com/en_US/cloud-infrastructure ). We also thank Achieve Life Sciences for useful discussions and support.

ASJC Scopus subject areas

Catalysis
General Chemistry
Biochemistry
Colloid and Surface Chemistry

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1021/jacs.9b09055

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abstract = "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.",

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AU - Bates, Phil

AU - Nunez, Gerardo Viedma

AU - Wonnacott, Susan

AU - Bermudez, Isabel

AU - Ciccotti, Giovanni

AU - Gallagher, Timothy

AU - Sessions, Richard B.

AU - Mulholland, Adrian J.

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

Abstract

Funding

ASJC Scopus subject areas

UN SDGs

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