Asymmetric Dynamics Between the Protomers of the σ2 Receptor Homodimer

The sigma-2 receptor (σ₂R/TMEM97) is a clinically relevant membrane protein involved in cholesterol regulation and overexpressed in cancer and neurodegenerative diseases. Despite its therapeutic potential, the dynamic mechanisms underlying σ₂R function and ligand binding remain poorly understood. Here, we combined adaptive sampling molecular dynamics simulations with quasi-anharmonic analysis and unsupervised machine learning method to investigate the conformational behavior of the σ₂R homodimer in both apo and cholesterol-bound states. Our results reveal asymmetric dynamics between the two protomers. This asymmetry is driven by anticorrelated helical motions and mutually exclusive salt bridge formation, including a switching mechanism between K₅₅-E₁₃₉ and D₁₂₂-R₁₄₀. Cholesterol binding further enhances this asymmetry by stabilizing one protomer and altering the dynamics of the other. Species-specific allosteric interaction between D₅₆-R₁₃₃ may be essential for the human σ₂R function. Additional lipid-protein interaction analysis highlights asymmetric membrane coupling in the bound state. These findings provide a plausible explanation for the receptor's dimeric nature, suggesting that ligand binding at one site may allosterically influence the apo protomer, thereby modulating receptor function. Our work provides new mechanistic insight into σ₂R function and highlights the importance of asymmetric dynamics.