Docking and Molecular Dynamic Simulation of ApoE isoforms to Trem2

Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with limited therapeutic options. The interaction between Triggering Receptor Expressed on Myeloid Cells 2 (TREM2), a critical microglial receptor, and Apolipoprotein E (ApoE), the strongest genetic risk factor for late-onset AD, plays a pivotal role in modulating immune responses in the brain. However, the structural and functional dynamics of TREM2-ApoE isoform interactions (ε2, ε3, and ε4) remain incompletely understood. Methods : Protein-protein docking using ClusPro was employed to model the interactions between wild-type TREM2 and the three ApoE isoforms (ε2, ε3, ε4) using crystallographic structures. Stability and structural dynamics of these complexes were analyzed using molecular dynamics simulations performed in GROMACS. Key parameters assessed included Root Mean Square Deviation (RMSD) for structural stability and Radius of Gyration for compactness. Results : Docking results indicated that ApoE ε3 had the lowest energy-weighted score, suggesting the most stable docking conformation. However, molecular dynamics simulations revealed that ApoE ε4 exhibited greater interaction robustness despite lower compactness. ApoE ε2 demonstrated the least stable interaction, characterized by significant variability in structural compactness. These findings highlight isoform-specific differences in TREM2-ApoE interactions, with ApoE ε4 exhibiting unique binding characteristics consistent with its strong association with AD risk. Conclusion : The therapeutic potential of modulating TREM2-ApoE interactions warrants exploration. Small molecules or biologics that selectively enhance or inhibit these interactions could represent novel strategies for mitigating AD risk or progression, particularly in individuals carrying the ApoE ε4 allele.