/To understand the super-inhibitory properties of the SLB peptides, we undertook molecular modeling on an insect SERCA, Ca-P60A, as well as protein-protein docking and molecular dynamics simulations of SERCA1a in an inhibitory complex with a SLB peptide. A molecular model of D. melanogaster calcium pump, Ca-P60A, was constructed using the Swiss-Model server (19) and rabbit SERCA1a in the E2 state as a template. The purpose of this exercise was to compare the binding groove for PLN and SLN between mammalian SERCA and the insect calcium pump Ca-P60A. The E2 state of SERCA was chosen as a model template because the binding groove for PLN and SLN is fully open. These calcium pump proteins are ~70% identical and the non-conserved residues are largely found on the surfaces of the protein (Figure 5). Indeed, the inhibitory binding groove (20–22) and the accessory binding site (23–25) for PLN and SLN are practically invariant between insects and mammals. In the inhibitory groove, sequence variations in Ca-P60A include Val^952, Ser^954, and Thr^955 at the base of M9, which correspond to Pro^952, Pro^954, and Met^955 in rabbit SERCA1a. These changes, particularly the proline residues in SERCA1a, appear to be responsible for the increased inhibitory capacity of the SLB peptides. At the accessory site, there is a single sequence variation Ala^273, which corresponds to Leu^273 in rabbit SERCA1a. Leu^273 was previously implicated in the interaction of PLN and SLN with the M3 accessory site of SERCA (23,24).