Cloud-based simulations on Google Exacycle reveal ligand modulation of GPCR activation pathways
Venue
Nature Chemistry, vol. 6 (2014), 15–21
Publication Year
2014
Authors
Kai Kohlhoff, Diwakar Shukla, Morgan Lawrenz, Gregory Bowman, David Konerding, Dan Belov, Russ Altman, Vijay Pande
BibTeX
Abstract
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.
