Cloud-based simulations on Google Exacycle reveal ligand modulation of GPCR activation pathways

Nat Chem. 2014 Jan;6(1):15-21. doi: 10.1038/nchem.1821. Epub 2013 Dec 15.


Simulations can provide tremendous insight into the atomistic details of biological mechanisms, but micro- to millisecond timescales are historically only accessible on dedicated supercomputers. We demonstrate that cloud computing is a viable alternative that brings long-timescale processes within reach of a broader community. We used Google's Exacycle cloud-computing platform to simulate two milliseconds of dynamics of a major drug target, the G-protein-coupled receptor β2AR. Markov state models aggregate independent simulations into a single statistical model that is validated by previous computational and experimental results. Moreover, our models provide an atomistic description of the activation of a G-protein-coupled receptor and reveal multiple activation pathways. Agonists and inverse agonists interact differentially with these pathways, with profound implications for drug design.

Publication types

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

MeSH terms

  • Internet*
  • Ligands
  • Markov Chains
  • Receptors, G-Protein-Coupled / metabolism*


  • Ligands
  • Receptors, G-Protein-Coupled

Associated data

  • PubChem-Substance/165246657
  • PubChem-Substance/165246658
  • PubChem-Substance/165246659
  • PubChem-Substance/165246660
  • PubChem-Substance/165246661
  • PubChem-Substance/165246662
  • PubChem-Substance/165246663
  • PubChem-Substance/165246664