= Solution
Use a <membrane topology> measurement on <v-SNARE> vesicles alone, so that partner binding cannot mask an outward-facing domain. A membrane-impermeant probe directed against the binding-domain region would label only the exposed population while vesicles remain intact. Compare that signal with total accessible <protein> after <lipid bilayer> disruption, using a trapped-lumen marker to check that the intact vesicles exclude the probe.
With comparable detection efficiencies and background subtraction,
$$
\boxed{f_{\rm outward}=\frac{S_{\rm intact}-S_{\rm background}}{S_{\rm permeabilized}-S_{\rm background}}.}
$$
An analogous <protease protection assay> compares external accessibility with total accessibility. In either approach, <lipid bilayer> leakage and steric masking must be distinguished from genuinely inward-facing <protein>.
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