AD‐Associated Variants Directly Impair Surface Interactions Between the Hydrophobic Site of TREM2 and the Hinge Region of ApoE

Background Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) and Apolipoprotein E (ApoE) are two of the strongest genetic risk factors for late-onset Alzheimer’s disease (AD), but while their interplay in microglial response to AD pathology is hotly studied, surprisingly little known about mechanism by which variants impair this role. Method To define structural AD-associated TREM2-ApoE interaction, we used sequence-based silico methods predict binding site between TREM2 ApoE, validated predicted with biolayer interferometry (BLI), then constructed initial models complex structures using identified APOE as restraints unbiased molecular docking methods. The top four were re-ranked comparing effect key residue mutations affinities calculated from dynamics-molecular mechanics Poisson-Boltzmann surface area (MD/MM-PBSA) free energy analyses measured BLI. final structure model provides further investigating effects interactions hydrophobic hinge region ApoE. Result Our iterative MD/MM-PBSA–BLI procedure generated an all-atom that replicates both engineered shows interaction centered apical sites consistent regions affected simulations individual proteins, biophysical studies truncated constructs a recently reported minimal active peptide sufficient stimulate its cytoprotective cytokine regulating roles primary microglia. Conclusion Iterative modeling affinity assays show impaired can be targeted generate novel therapeutics AD.