Binding interactions of epididymal protease inhibitor and semenogelin-1: a homology modeling, docking and molecular dynamics simulation study

Epididymal protease inhibitor (EPPIN) that is located on the sperm surface and specific to the male reproductive system is a non-hormonal contraceptive target, since the binding of EPPIN with the seminal plasma protein semenogelin-1 (SEMG1) causes a loss of sperm function. Here, we investigated the binding interactions between EPPIN and SEMG1 by homology modeling, docking and molecular dynamics simulation. Since no crystal structure was reported for EPPIN, its 3D structure was constructed by homology modeling and refined by dynamics simulation, illustrating the C-terminus domain of EPPIN could bind with its N-terminus domain through the residues 30–32 and 113–116. The binding interaction of SEMG110-8 peptide and EPPIN was investigated by Z-DOCK and dynamics simulation. After evaluating the models according to the calculated binding free energies, we demonstrated that C-terminus domain of EPPIN was important for the binding of SEMG1 via residues Tyr107, Gly112, Asn116, Gln118 and Asn122, while residue Arg32 in N-terminus domain also had contribution for their binding interaction. Additionally, the binding pocket of EPPIN was defined according to these key residues and verified by molecular docking with reported inhibitor EP055, suggesting that the pocket formed by Arg32, Asn114, Asn116, Phe117 and Asn122 could be important for the design of new ligands. This study might be helpful for the understanding of biological function of EPPIN and would encourage the discovery of non-hormonal contraceptive leads/drugs in the future.