While performing MI calculations on large structures, such as the SERCA pump, we had initially aligned the structures against a reference structure (for instance, the first frame of the trajectory). We observed that this approach tended to cause the MI algorithm to predict anomalously large correlations at the distant extremities of the protein, as the larger structures would exhibit "breathing" motions upon structural alignment. Since large groups of atoms at the protein extremities would exhibit concerted motions that would disproportionally bias the algorithm, causing it to indicate an unrealistically large correlated motion for these groups of atoms, compared to the relatively stationary atoms at the protein core.