Triggering receptor expressed on myeloid cells 2 (TREM2) is a central regulator of microglia activation and lipid metabolism, linking immune signaling to neurodegenerative and metabolic disease. While experimental and clinical studies have greatly expanded our understanding of TREM2 biology, the molecular principles governing its conformational plasticity, interactions with membranes and ligands, and the behavior of disease-associated variants remain unresolved. Recent molecular dynamics (MD) simulations of TREM2 have provided an atomistic view of these mechanisms, revealing novel structural, dynamic, and energetic features inaccessible to experimental methods alone. In this Review, we comprehensively assess these MD studies, integrating mechanistic insights across protein domains and modeling approaches. We critically evaluate simulations that describe how missense mutations uniquely perturb TREM2's complementarity-determining region (CDR) ligand-binding sites, transmembrane domain signaling motifs, and multimerization interfaces. We further elucidate how simulations capture novel CDR2 dynamics that cannot be resolved using traditional experimental methods, and how in silico findings align with data from experimental binding assays and crystallographic studies. Finally, we outline how rigorously designed simulations—performed with sufficient replicates and timescales—can guide rational engineering of small-molecule and peptide modulators targeting TREM2, advancing therapeutic strategies that can restore TREM2-mediated lipid sensing and signaling in metabolic and neurodegenerative diseases.
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