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.2023 Sep 1;13(1):14382.
doi: 10.1038/s41598-023-41365-1.

Interactions of the male contraceptive target EPPIN with semenogelin-1 and small organic ligands

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Interactions of the male contraceptive target EPPIN with semenogelin-1 and small organic ligands

Antoniel A S Gomes et al. Sci Rep..

Abstract

Novel male contraceptives will promote gender equality in sharing contraceptive responsibility. The sperm-associated protein epididymal protease inhibitor (EPPIN) is a promising target for non-hormonal male contraception. EPPIN interacts with the semen coagulum protein semenogelin-1 (SEMG1) on the sperm surface, leading to transient inhibition of sperm motility after ejaculation. Small organic molecules targeting EPPIN's SEMG1-binding are under development as male contraceptives. Here, we combined computational approaches to uncover key aspects underlying EPPIN binding to SEMG1 and small organic ligands. We generated a human EPPIN model showing a typical arrangement of the WFDC (Whey-acid four disulfide core)-type and Kunitz-type domains, connected by a hinge region. Determining the EPPIN model's intrinsic motion by molecular dynamics simulations and normal mode analysis revealed a conformation, presenting a binding pocket that accommodates SEMG1Glu229-Gln247, EP055, and EP012. EPPIN's residues Phe63 and Lys68 (WFDC domain), Asp71 (hinge region), and Asn113, Asn114, and Asn115 (Kunitz domain) were identified as hot spots for SEMG1, EP055, and EP012 binding. Moreover, hydrophobic and hydrophilic residues in the WFDC and Kunitz domains allow plasma membrane anchoring, orienting the EPPIN binding pocket to the solvent. Targeting EPPIN's essential residues for its biomolecular interactions may improve the rational design of EPPIN ligands as spermiostatic compounds.

© 2023. Springer Nature Limited.

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Conflict of interest statement

Michael G. O'Rand has stock ownership in Eppin Pharma Inc. Dr. O'Rand receives no salary from Eppin Pharma. He is retired from the University but retains his association with UNC and the Department of Cell Biology & Physiology. Katherine G. Hamil has stock ownership in Eppin Pharma Inc. She is a full-time employee of Eppin Pharma. This does not alter our adherence to policies on sharing data and materials. There are no restrictions on sharing our data. The other authors declare no competing interests.

Figures

Figure 1
Figure 1
Structural aspects of the full-length EPPIN model. (a) The initial model of EPPIN generated by homology modeling, highlighting the N-terminal, the hinge segment, and the C-terminal domains shown as a cartoon in blue, brown, and green, respectively. Disulfide bonds are presented as sticks, with sulfur in yellow. (b) Gibbs free energy landscape of the model after conformational exploration of the three independent replicas of MD simulations, using the distances of Phe63 to the Asn repeat and the interdomain angle (θ) as variables to classify all conformations. Three states were observed, with representative conformations named Cla, Clb, and Clc, shown by empty triangles. The initial structure (model) is shown as a filled triangle. (c) Temporal RMSD and (d) Rg calculations for each replica are shown in blue, green, and brown.
Figure 2
Figure 2
FTMap of the three main states of the EPPIN model. Cla, Clb, and Clc were used for calculations to determine the most important residues for hydrogen bonding interactions. The upper panel shows the states (a) Cla, (b) Clb, and (c) Clc, presenting the position of residues with a high percentage to form hydrogen bonds to ligands. (d) The lower panel shows the percentage of hydrogen bonding interactions with ligands for each residue of Cla (blue bars), Clb (green bars), and Clc (brown bars). WFDC (blue) and Kunitz (green) domains and hinge segment (brown) are shown.
Figure 3
Figure 3
Interaction between the full-length EPPIN model with the endogenous ligand SEMG1. (a) Docking 1 of Cla (blue line) and Clc (green line) during 500 ns of MD simulation. (b) The final orientation of Docking 1 of Cla with EPPIN is shown in detail. EPPIN WFDC domain (blue), Kunitz domain (green) and hinge segment (brown), and SEMG1-E2Q peptide (purple) are shown. (c) Time evolution of the minimal distance between EPPIN Asp71 (blue line), Asn113 (green line), and Asn114 (brown line), and SEMG1 Gln235 is shown. (d) The spatial orientation of such residues is shown in detail.
Figure 4
Figure 4
Interaction between the full-length EPPIN model with the exogenous ligand EP055. (a) Temporal RMSD of Docking 1 of Cla (blue line), Docking 2 of Cla (green line), and Docking 1 of Clc (brown line) during 500 ns of MD simulation. (b) Docking 1 and (d) Docking 2 of Cla with EPPIN are shown. EPPIN WFDC domain (blue), Kunitz domain (green) and hinge segment (brown), and EP055 ligand (purple) are shown. Time evolution of the minimal distance between important residues of EPPIN for (f) Docking 1 and (g) are shown, with (c,e) their spatial orientation shown in detail.
Figure 5
Figure 5
Interaction model of the full-length EPPIN model with the plasma membrane. The complex EPPIN/SEMG1 peptide was selected for anchoring in a 100% POPC bilayer. EPPIN WFDC domain (blue), Kunitz domain (green) and hinge segment (brown), SEMG1-E2Q peptide (purple), and POPC (yellow) are shown. (a) The initial orientation of the complex was predicted by the OPM server, with (b) its final orientation obtained after 100 ns of MD simulation. (c) Hydrophobic and (d) polar residues of EPPIN were identified as important in the interaction and anchoring on the plasma membrane.
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