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Molecular dynamics study reveals key disruptors of MEIG1-PACRG interaction
Timothy Hasse1, Zhibing Zhang2,3, Yu-Ming M Huang1
1Department of Physics and Astronomy, Wayne State University, Detroit, Michigan, USA.
Abstract:
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.
Insights
Understanding MEIG1 and PACRG protein interactions is key for male contraception. This study used simulations to show how mutations disrupt sperm formation, identifying PACRG as a potential drug target.
Area of Science:
- Biochemistry
- Molecular Biology
- Reproductive Biology
Background:
- The interaction between meiosis-expressed gene 1 (MEIG1) and Parkin co-regulated gene (PACRG) proteins is essential for mature sperm formation.
- Targeting MEIG1 or PACRG presents a potential strategy for male contraceptive development.
- Specific mutations (W50A, Y68A) in MEIG1 disrupt MEIG1-PACRG interactions, leading to defective sperm, but the precise mechanisms remain unclear.
Purpose of the Study:
- To elucidate the molecular dynamics of MEIG1-PACRG interactions and how specific mutations affect protein binding.
- To identify potential drug targets for male contraception based on the MEIG1-PACRG interaction surface.
Main Methods:
- Gaussian-accelerated molecular dynamics (GaMD) simulations were employed to analyze protein dynamics.
- Post-simulation analysis was conducted to investigate the effects of W50A and Y68A mutations on MEIG1-PACRG binding.
Main Results:
- The W50A and Y68A mutations destabilize the interface between MEIG1 and PACRG proteins.
- The Y68A mutation exhibits a more pronounced disruptive effect than W50A due to stronger disruption of polar interactions with PACRG.
- Similar dynamic properties were observed in both human and mouse protein models, validating the use of mouse models for human relevance.
- A potential ligand-binding pocket was identified on the MEIG1-PACRG interaction surface, with PACRG presenting more suitable pockets for drug targeting.
Conclusions:
- The study provides fundamental insights into MEIG1-PACRG protein dynamics and the impact of mutations on their interaction.
- PACRG is identified as a promising target for developing novel male contraceptive agents.
- These findings pave the way for future drug discovery efforts aimed at male-based contraception.
