title: Cloud-based simulations on Google Exacycle reveal ligand modulation of GPCR activation pathways.
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.
authors.affiliation: Department of Bioengineering, Stanford University, 450 Serra Mall, Stanford, CA 94305, USA.|Google Inc., 1600 Amphitheatre Parkway, Mountain View, CA 94043, USA.
authors.forename: Kai J
authors.initials: KJ
authors.lastname: Kohlhoff
authors.affiliation: Department of Bioengineering, Stanford University, 450 Serra Mall, Stanford, CA 94305, USA.|Department of Chemistry, Stanford University, 450 Serra Mall, Stanford, CA 94305, USA.
authors.forename: Diwakar
authors.initials: D
authors.lastname: Shukla
authors.affiliation: Department of Chemistry, Stanford University, 450 Serra Mall, Stanford, CA 94305, USA.
authors.forename: Morgan
authors.initials: M
authors.lastname: Lawrenz
authors.affiliation: Department of Chemistry, Stanford University, 450 Serra Mall, Stanford, CA 94305, USA.
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Bowman
authors.affiliation: Google Inc., 1600 Amphitheatre Parkway, Mountain View, CA 94043, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Konerding
authors.affiliation: Google Inc., 1600 Amphitheatre Parkway, Mountain View, CA 94043, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Belov
authors.affiliation: Department of Bioengineering, Stanford University, 450 Serra Mall, Stanford, CA 94305, USA.|Department of Genetics, Stanford University, 450 Serra Mall, Stanford, CA 94305, USA.
authors.forename: Russ B
authors.initials: RB
authors.lastname: Altman
authors.affiliation: Department of Chemistry, Stanford University, 450 Serra Mall, Stanford, CA 94305, USA.
authors.forename: Vijay S
authors.initials: VS
authors.lastname: Pande
mesh_terms: D020407:Internet; D008024:Ligands; D008390:Markov Chains; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*
chemical_list: D008024:Ligands; D043562:Receptors, G-Protein-Coupled