Investigating Small-Molecule Ligand Binding to G Protein-Coupled Receptors with Biased or Unbiased Molecular Dynamics Simulations

Methods Mol Biol. 2018;1705:351-364. doi: 10.1007/978-1-4939-7465-8_17.


An increasing number of G protein-coupled receptor (GPCR) crystal structures provide important-albeit static-pictures of how small molecules or peptides interact with their receptors. These high-resolution structures represent a tremendous opportunity to apply molecular dynamics (MD) simulations to capture atomic-level dynamical information that is not easy to obtain experimentally. Understanding ligand binding and unbinding processes, as well as the related responses of the receptor, is crucial to the design of better drugs targeting GPCRs. Here, we discuss possible ways to study the dynamics involved in the binding of small molecules to GPCRs, using long timescale MD simulations or metadynamics-based approaches.

Keywords: Allosteric communication; Enhanced-sampling methods; GPCRs; Interaction fingerprints; Ligand binding; Molecular dynamics; Small-molecule drugs.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, N.I.H., Extramural

MeSH terms

  • Allosteric Regulation
  • Binding Sites
  • Drug Discovery* / methods
  • Ligands*
  • Molecular Dynamics Simulation*
  • Protein Binding
  • Quantitative Structure-Activity Relationship
  • Receptors, G-Protein-Coupled / chemistry*


  • Ligands
  • Receptors, G-Protein-Coupled