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. Anton has made possible simulations in which drugs spontaneously associate with GPCRs to achieve bound conformations that match experimental structures almost perfectly. Simulations on Anton have also captured transitions of a GPCR between its active and inactive structures, allowing us to characterize the mechanism of receptor activation. Our results, together with complementary experimental data, suggest opportunities for the design of drugs that achieve greater specificity and control receptor signaling more precisely.
Sunday, April 08, 2012
Free and open to the public