Opioids are highly effective pain killers, but can be deadly if overdosed. Thus, a clear understanding of opioid-receptor unbinding mechanisms and kinetics are highly desirable in developing or administering antidotes. However, this task is difficult to achieve in both experiments and computer simulations. Molecular details of the dissociation process are almost impossible to capture in experiments, while the relevant time scales are beyond the capability of brute force molecular dynamics (MD) simulation, deeming the approach ineffective. In this work, we employed weighted ensemble (WE) method, an enhanced sampling technique, to look into the unbinding pathways and kinetics of fentanyl and its derivatives from the mu-opioid receptor (mOR). Since WE method focuses on sampling rare events, dissociation pathways and rate constants can be determined rapidly. Our intial WE results showed the posibility of multiple unbinding pathways as well as the dependency of kinetics rates on such pathways.

Elucidating mu-opioid receptor-agonist interactions and unbinding pathways by weighted ensemble molecular dynamics method

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.