Macrophage plasticity is essential for maintaining immune homeostasis, and the Triggering Receptor Expressed
on Myeloid Cells 2 (TREM2) plays a central role in enabling these cells to toggle between pro- and antiinflammatory
states. Genetic variation and ligand diversity in TREM2 are strongly linked to dysregulated
inflammation in neurodegeneration, cancer, and infection, yet the molecular mechanisms that connect these
factors to signaling remain poorly understood. In this talk, I will present a multiscale computational framework
that unites bioinformatics, molecular dynamics, and structural biophysics to elucidate how sequence variation,
ligand binding, and membrane organization converge on TREM2 to regulate macrophage activation. Atomistic
simulations of disease-associated variants reveal how single-residue changes reshape the conformational
ensemble of TREM2 and alter its signaling-competent states. Comparative simulations of TREM2 bound to
diverse ligands—including apolipoproteins and phospholipids—highlight shared versus ligand-specific binding
mechanisms that bias downstream immune polarization. Finally, coarse-grained simulations of full-length
TREM2–DAP12 complexes embedded in realistic membranes uncover how lipid composition and receptor
multimerization modulate interfacial stability and signaling strength. Together, these studies establish a
predictive, molecular-level framework for decoding TREM2-mediated signaling in innate immunity and lay the
groundwork for rational design of therapeutics that selectively modulate macrophage-driven inflammation across
disease contexts.
