The Origin and Evolution of Sex Peptide and Sex Peptide Receptor Interactions.

Post-mating responses play a vital role in successful reproduction across diverse species. In fruit flies, sex peptide (SP) binds to sex peptide receptor (SPR), triggering a series of post-mating responses. However, the origin of SPR predates the emergence of SP. The evolutionary origins of the interactions between SP and SPR and the mechanisms by which they interact remain enigmatic. In this study, we used ancestral sequence reconstruction, AlphaFold2 predictions, and molecular dynamics simulations to study SP-SPR interactions and their origination. Using AlphaFold2 and long-time molecular dynamics (MD) simulations, we demonstrate the structure and dynamics of SP-SPR interactions. We show that SP potentially binds to the ancestral states of Diptera SPR. Notably, we found that only a few amino acid changes in SPR are sufficient for the formation of SP-SPR interactions. Ancestral sequence reconstruction and MD simulations further reveal that SP-SPR interacts through residues that are mostly located at the SPR interface of an ancestral ligand, myoinhibitory peptides (MIPs). We propose a potential mechanism whereby SP-SPR interactions arise from pre-existing MIP-SPR interface as well as early chance events that created novel SP-specific SP-SPR interactions. Our findings provide new insights into the origin and evolution of SP-SPR interactions and their relationship with MIP-SPR interactions.