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Accelerated molecular dynamics simulations of ligand binding to a muscarinic G-protein-coupled receptor

  • Kalli Kappel (a1), Yinglong Miao (a2) and J. Andrew McCammon (a1) (a2) (a3)

Abstract

Elucidating the detailed process of ligand binding to a receptor is pharmaceutically important for identifying druggable binding sites. With the ability to provide atomistic detail, computational methods are well poised to study these processes. Here, accelerated molecular dynamics (aMD) is proposed to simulate processes of ligand binding to a G-protein-coupled receptor (GPCR), in this case the M3 muscarinic receptor, which is a target for treating many human diseases, including cancer, diabetes and obesity. Long-timescale aMD simulations were performed to observe the binding of three chemically diverse ligand molecules: antagonist tiotropium (TTP), partial agonist arecoline (ARc) and full agonist acetylcholine (ACh). In comparison with earlier microsecond-timescale conventional MD simulations, aMD greatly accelerated the binding of ACh to the receptor orthosteric ligand-binding site and the binding of TTP to an extracellular vestibule. Further aMD simulations also captured binding of ARc to the receptor orthosteric site. Additionally, all three ligands were observed to bind in the extracellular vestibule during their binding pathways, suggesting that it is a metastable binding site. This study demonstrates the applicability of aMD to protein–ligand binding, especially the drug recognition of GPCRs.

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This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted re-use, distribution, and reproduction in any medium, provided the original work is properly cited.

Corresponding author

* Author for correspondence: Y. Miao, Howard Hughes Medical Institute, University of California at San Diego, La Jolla, CA 92093, USA. Tel.: 1-850-822-0255; Fax: 1-858-534-4974; Email: yimiao@ucsd.edu

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Accelerated molecular dynamics simulations of ligand binding to a muscarinic G-protein-coupled receptor

  • Kalli Kappel (a1), Yinglong Miao (a2) and J. Andrew McCammon (a1) (a2) (a3)

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