How Drugs Bind and Control Their Targets: Characterizing GPCR Signaling using Anton, a Special-Purpose Supercomputer for Molecular Dynamics Simulations

Roughly one-third of all drugs act by binding to G-protein-coupled receptors (GPCRs) and either triggering or preventing receptor activation, but the process by which they do so has proven difficult to determine using either experimental or computational approaches. We recently completed a special-purpose machine, named Anton, that uses a combination of novel algorithms and application-specific hardware to accelerate molecular dynamics simulations by orders of magnitude, enabling all-atom protein simulations as long as a millisecond (Science 330:341-6, 2010). Anton has made possible simulations in which drugs spontaneously associate with GPCRs to achieve bound conformations that match crystal structures almost perfectly (PNAS 108:13118-23, 2011; Nature 482:552-6, 2012). Simulations on Anton have also captured transitions of a GPCR between its active and inactive states, allowing us to characterize the mechanism of receptor activation (Nature 469:236-40, 2011; PNAS 108:18684-9, 2011). Our results, together with complementary experimental data, suggest opportunities for the design of drugs that achieve greater specificity and control receptor signaling more precisely.
Since joining D. E. Shaw Research as its first hire, Ron Dror has served as Senior Research Scientist and deputy to Chief Scientist David E. Shaw, overseeing various projects in computational structural biology and high-performance computing. He earned a Ph.D. in Electrical Engineering and Computer Science at MIT and an M.Phil. in Biological Sciences as a Churchill Scholar at the University of Cambridge.