Streptavidin isCA∆-SIDC. Streptavidin is a tetramer that features a dimer-of-dimers topology (inset structure in Figure ). Thus, dissociation to dimers should be the preferred fragmentation pathway for native-like SID (Figure ). This is the case for SA, as seen in Figure , which reflects dimer as the primary dissociation pathway at low cone voltages. This trend is stable up to a cone voltage of approximately 90 V, at which point the normalized dimer intensity decreases as the cone voltage continues to increase. This suggests that either secondary fragmentation begins to occur when the sum of the isCA and SID activation exceeds a threshold, or the initial quaternary structure rearranges to a non-native-like structure that becomes apparent by the change in SID fragmentation and/or the change in drift time and product charge state. The CIx plot overlay in Figure and S2, suggest that the drift time is stable until a cone voltage of 120 -130 V. Between that point and the max cone voltage of 160 V, the drift time shifts to lower values, reflective of a more compact, non-native-like structure. Clearly, SID, as a diagnostic tool, is sensitive enough to detect excess energy deposition in the source, or rearranged quaternary structure, before ion mobility hints at the possibility that something has changed. As seen in Figure , as the dimer's contribution to normalized intensity decreases, the contribution from monomer and trimer increase. The slope of the monomer increase tracks with dimer decrease and is steeper than trimer increase, suggesting secondary fragmentation. The increase in trimer (and the portion of monomer produced from tetramer, not dimer) is a strong indicator that the weak subunit interfaces between dimer subunits, which are the most likely to be cleaved by SID, have been altered in a way that results in non-native SID, the mobiligram for which can be seen in Figure .