Classical opioid receptor drugs, like morphine and its derivatives, have been used for centuries to manage chronic pain despite frequent occurrence of adverse effects, including addiction, respiratory depression, vomiting, constipation, and severe sedation. A recent campaign to identify μ-opioid receptor agonists that are effective as analgesics but devoid of side effects led to the discovery of a selective and potent analogue of the non-nitrogenous ligand herkinorin, a semi-synthetic derivative of the naturally occurring κ-opioid receptor agonist salvinorin A. Several different crystal structures of opioid receptors have offered insight into the binding of opioid ligands with positively charged amine groups to their receptors. These ligands all bind at a well-characterized orthosteric binding pocket through a salt-bridge interaction between the amino group and a conserved aspartic acid in transmembrane helix 3 of the receptor. The obvious absence of this interaction in the binding of non-nitrogenous ligands, and the uncertainty surrounding both their binding pocket and energetically preferred poses, prompted us to carry out all-atom multiple-walker metadynamics simulations to study the binding of herkinorin analogues to a fully flexible μ-opioid receptor in an explicit lipid-water environment. Clustering of all the bound conformations sampled reveals different, but energetically indistinguishable, binding modes for the studied ligands. Analysis of the ligand-receptor interactions formed by each conformation in the various clusters suggests testable hypotheses of molecular determinants responsible for the affinity and/or efficacy of herkinorin analogues.