Understanding the binding mechanisms of Alzheimer risk factor TREM2 in lipid bilayer using multi-scale molecular dynamics simulations

Alzheimers disease (AD) is a widespread neurodegenerative condition affecting millions globally. Recent research has implicated variants of the triggering receptor ex-pressed in myeloid cells 2 (TREM2) as risk factors for AD. TREM2, an immunomodula-tory receptor on microglial surfaces, plays a pivotal role in regulating microglial activa-tion by associating with DNAX-activation protein 12 (DAP12). Despite its significance, the mechanism underlying the formation of the complex between the transmembrane domains (TMDs) of TREM2 and DAP12 remains unclear. This study employs multi-scale molecular dynamics (MD) simulations to investigate three TMD complex models, including two derived from experiments and one generated by AlphaFold2. Conducted within a lipid membrane consisting of an 80:20 mixture of phosphatidylcholine (POPC) and cholesterol, our analysis reveals hydrogen bonding interactions between K26 of TREM2 and D16 of DAP12 in all three models, consistent with previous experimen-tal findings. Our results elucidate the different spatial conformations observed in the models and offer insights into the structure of the TREM2/DAP12 TMD complex. Furthermore, we elucidate the role of charged residues in the assembly structure of the complex within the lipid membrane. These findings enhance our understanding of the molecular mechanism governing TREM2/DAP12 complex formation, providing a foundation for designing novel therapeutic strategies to address AD and other neu-rodegenerative diseases. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=184 SRC="FIGDIR/small/584168v2_ufig1.gif" ALT="Figure 1"> View larger version (63K): org.highwire.dtl.DTLVardef@15c1e93org.highwire.dtl.DTLVardef@db697eorg.highwire.dtl.DTLVardef@eb0914org.highwire.dtl.DTLVardef@a12b9a_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIDifferent TREM2/DAP12 complexes are generated using experimental PDB structures or AlphaFold2 C_LIO_LILong time coarse-grained MD simulations are used for getting the sys-tems stable C_LIO_LIAtomistic detailed complex structures are captured using all-atom sim-ulation C_LIO_LIProvides mechanistic insight into TREM2 transformation from its un-bound state to bounded state C_LIO_LIOffers novel insights into the molecular basis of TREM2/DAP12 sig-nalling pathway C_LI