The Class F G protein-coupled receptors (GPCRs) include Smoothened and the ten Frizzled receptors, which are major cell membrane receptors in the Hedgehog and Wnt signalling pathways respectively and of enormous interest in embryonic development and as therapeutic targets in cancer. Recent crystal structures of Smoothened provide the opportunity to investigate the structural biology of Class F GPCRs in more detail, in turn, informing the development of therapeutics. A key question in this area is how one receptor may trigger distinct pathways - particularly relevant for Wnt signalling, in which signals may be transduced from a Frizzled via Dishevelled or G proteins, depending on the context. In this study, we employ adiabatic biased molecular dynamics and umbrella sampling to investigate the activation of Smoothened and Frizzled-7 in both the native state and bound to endogenous ligands, as well as how the clinically used Smoothened antagonist vismodegib alters this signalling. The results highlight key energetic barriers in the activation of these receptors, and the molecular features of the receptors mediating these barriers, demonstrating our approach as a robust means of investigating signalling through these receptors.