(7o) Machine Learning and Molecular Dynamics Map Conformational Landscape of µ-Opioid Receptor

The µ Opioid Receptor (µOR) is a key mediator of pain and critical target for analgesic medications. The current generation of opiates â?? drugs that bind to µOR â?? are beset by dangerous side effects such as respiratory depression and addiction. In this work, molecular dynamics (MD) simulations are deployed to generate a high-resolution map of the conformational landscape of µOR. By seeding such simulations from the two X-Ray crystal structures of µOR, we not only identify key intermediates between these two structures, but also reveal new metastable states that are unforeseeable from crystallography alone. The application of Markov State Models with machine learning demonstrates tight coupling between the orientations of opiates in the binding pocket with downstream changes in the receptorâ??s overall conformation. This clearer model of µOR dynamics may be useful to medicinal chemists in developing opiates with a more desirable therapeutic profile.

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