Fig. 5

Molecular interactions of compound M23 with NHR2 from MD simulations of free ligand diffusion. On the left side, the heavy-atom particle density of M23 around the NHR2 tetramer is depicted in a color-coded manner (see color scale). When accounting for the internal symmetry of NHR2, two primary binding epitopes are identified (black rectangles). The left blowup shows M23 binding to epitope I, where the isopropyl group of M23 is buried between the NHR2 helices, allowing the compound to interact with the hotspot residues W498 and W502. The right blowup shows M23 bound to the protein-protein interface of NHR2 with transcription factor-12¹¹ (epitope II). Here, the benzodioxepane ring is partially buried between the helices, while the thiazolopyrimidine ring is bound to a hydrophobic methionine-rich patch.