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

  • Kristen A. Marino
  • Marta FilizolaEmail author
Part of the Methods in Molecular Biology book series (MIMB, volume 1705)


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.

Key words

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



This work was supported by National Institutes of Health grants MH107053, DA026434, and DA034049. Computations discussed here were run on resources available through (a) the Scientific Computing Facility at the Icahn School of Medicine at Mount Sinai, (b) the Extreme Science and Engineering Discovery Environment (XSEDE) under MCB080077, which is supported by National Science Foundation grant number ACI-1053575, and (c) the Pittsburgh Supercomputing Center which provided Anton computer time (under PSCA14006) through grant R01GM116961 from the National Institutes of Health. The Anton machine at PSC was generously made available by D.E. Shaw Research


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Copyright information

© Springer Science+Business Media LLC 2018

Authors and Affiliations

  1. 1.Department of Pharmacological SciencesIcahn School of Medicine at Mount SinaiNew YorkUSA

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