Journal
QUARTERLY REVIEWS OF BIOPHYSICS
Volume 48, Issue 4, Pages 479-487Publisher
CAMBRIDGE UNIV PRESS
DOI: 10.1017/S0033583515000153
Keywords
Ligand binding; G-protein coupled receptor; M3 muscarinic receptor; accelerated molecular dynamics; enhanced sampling
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Funding
- NSF [MCB1020765]
- NIH [GM31749]
- Howard Hughes Medical Institute
- Center for Theoretical Biological Physics (CTBP)
- National Biomedical Computation Resource (NBCR)
- Gordon and Stampede supercomputers through the Extreme Science and Engineering Discovery Environment (XSEDE) [TG-MCB140011]
- Hopper and Edison supercomputers through the National Energy Research Scientific Computing Center (NERSC) [m1395]
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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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