Targeting MEIG1 and PACRG Protein Interaction for Male Contraception by Molecular Modeling

Interactions between the meiosis expressed gene 1 (MEIG1) and Parkin co-regulated gene (PACRG) protein are critical for mature sperm cell formation, and targeting either protein could be a viable contraceptive strategy. To gain insights into the underlying mechanism and dynamics of MEIG1-PACRG binding, we applied Gaussian accelerated molecular dynamics (GaMD) simulations and post-GaMD analysis. Our results suggest that MEIG1 residues W50 and Y68 play a crucial role in stabilizing MEIG1-PACRG binding by forming a complex network of interactions with PACRG. Moreover, our work demonstrates similar dynamic properties between human and mouse models, implying that the findings from mouse proteins can be applied to the proteins in developing human sperm. Using the Fpocket binding pocket detection algorithm, we identified a primary ligand binding pocket on the MEIG1 and PACRG interaction surface near W50 and Y68. We then performed virtual screening and molecular docking to test nearly one million drug-like compounds for their ability to bind the targeted pocket. This work provides a critical step forward in the development of male-based birth control by deepening our understanding of the MEIG1 and PACRG interaction and narrowing the list of potential drug candidates for future studies.