Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 115, Issue 12, Pages 3036-3041Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1800756115
Keywords
enhanced sampling; protein binding; pathways; biomolecular recognition; GPCR signaling
Categories
Funding
- Extreme Science and Engineering Discovery Environment Award [TG-MCA93S013]
- National Energy Research Scientific Computing Center project [M2874]
- NSF [MCB1020765]
- NIH [GM31749]
- Howard Hughes Medical Institute
- National Biomedical Computation Resource
- American Heart Association Award [17SDG33370094]
- College of Liberal Arts and Sciences at the University of Kansas
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM031749] Funding Source: NIH RePORTER
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Protein-protein binding is key in cellular signaling processes. Molecular dynamics (MD) simulations of protein-protein binding, however, are challenging due to limited timescales. In particular, binding of the medically important G-protein-coupled receptors (GPCRs) with intracellular signaling proteins has not been simulated with MD to date. Here, we report a successful simulation of the binding of a G-protein mimetic nanobody to the M-2 muscarinic GPCR using the robust Gaussian accelerated MD (GaMD) method. Through long-timescale GaMD simulations over 4,500 ns, the nanobody was observed to bind the receptor intracellular G-protein-coupling site, with a minimum rmsd of 2.48 angstrom in the nanobody core domain compared with the X-ray structure. Binding of the nanobody allosterically closed the orthosteric ligand-binding pocket, being consistent with the recent experimental finding. In the absence of nanobody binding, the receptor orthosteric pocket sampled open and fully open conformations. The GaMD simulations revealed two low-energy intermediate states during nanobody binding to the M-2 receptor. The flexible receptor intracellular loops contribute remarkable electrostatic, polar, and hydrophobic residue interactions in recognition and binding of the nanobody. These simulations provided important insights into the mechanism of GPCR-nanobody binding and demonstrated the applicability of GaMD in modeling dynamic protein-protein interactions.
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