Hydrogen/deuterium exchange detected by mass spectrometry (HDX-MS) provides valuable information on protein structure and dynamics. Although HDX-MS data is often interpreted using crystal structures, it was suggested that conformational ensembles produced by molecular dynamics simulations yield more accurate interpretations. In this paper, we analyse the complement protein C3d through HDX-MS data and evaluate several interpretation methodologies, using an existing prediction model to derive HDX-MS data from protein structure. We perform an HDX-MS experiment on C3d and, then, to interpret and refine the obtained data, we look for a conformation (or conformational ensemble) of C3d that allows computationally replicating this data. First, we confirm that crystal structures are not a good choice. Second, we suggest that conformational ensembles produced by molecular dynamics simulations might not always be satisfactory either. Finally, we show that coarse-grained conformational sampling of C3d produces a conformation from which the HDX-MS data can be replicated and refined.