MD Simulations of Human Sigma-1 Receptor Trimer Uncover Cholesterol-Dependent Stabilization and Ligand-Specific Dynamics.

The sigma-1 receptor (S1R) is an endoplasmic reticulum transmembrane protein implicated in a wide range of physiological and pathological processes, including neurodegeneration, cancer, and pain modulation. Although X-ray crystallography has revealed S1R as a trimeric assembly with a distinctive triangular architecture, the dynamic behavior of this oligomeric state and its modulation by ligands and membrane composition remain poorly understood. In particular, agonists and antagonists have been experimentally proved to differentially regulate S1R oligomerization, although the underlying molecular mechanisms are still obscure. Here, we present one of the first atomistic molecular dynamics studies of the human S1R trimer; the system is embedded in a cholesterol-containing lipid membrane, which provides a more physiologically relevant environment. Using a total of 12 μs of simulation time, we investigate the impact of membrane composition, with a specific focus on cholesterol, as well as the conformational response of S1R to pharmacologically distinct ligands: the agonist (+)-pentazocine and the antagonist haloperidol. Our simulations reveal how ligands can alter S1R interprotomer interaction through a mechanism involving the β6 strand of the protein and in particular W136, data that correlate with experimentally observed differences in S1R oligomerization. These findings provide new molecular-level insights into S1R regulation and establish a framework for rationalizing the distinct functional outcomes induced by agonists and antagonists.