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Interactions between the meiosis‐expressed gene 1 (MEIG1) and Parkin co‐regulated gene (PACRG) protein are critical in the formation of mature sperm cells. Targeting either MEIG1 or PACRG protein could be a contraceptive strategy. The W50A and Y68A mutations on MEIG1 are known to interrupt the MEIG1–PACRG interactions resulting in defective sperm cells. However, the details about how the mutants disrupt the protein–protein binding are not clear. In this study, we reveal insights on MEIG1 and PACRG protein dynamics by applying Gaussian‐accelerated molecular dynamics (GaMD) simulations and post‐GaMD analysis. Our results show that the mutations destabilize the protein–protein interfacial interaction. The effect of the Y68A mutation is more significant than W50A as Y68 forms stronger polar interactions with PACRG. Because both human and mouse models demonstrate similar dynamic properties, the findings from mouse proteins can be applied to the human system. Moreover, we report a potential ligand binding pocket on the MEIG1 and PACRG interaction surface that could be a target for future drug design to inhibit the MEIG1–PACRG interaction. PACRG shows more qualified pockets along the protein–protein interface, implying that it is a better target than MEIG1. Our work provides a fundamental understanding of MEIG1 and PACRG protein dynamics, paving the way for drug discovery in male‐based contraception.