K. J. Kohlhoff*, D. Shukla*, M. Lawrenz*, G. R. Bowman, D. E. Konerding, D. Belov, R. B. Altman & V. S. Pande
Nature Chemistry 6, 15–21 (2014) doi:10.1038/nchem.1821 *denotes co-first author
Publication year: 2014


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

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