Allosteric response to ligand binding: Molecular dynamics study of the N-terminal domains in IP receptor

Inositol 1,4,5-trisphosphate (IP₃) receptor (IP₃R) is a huge tetrameric intracellular Ca²⁺ channel that mediates cytoplasmic Ca²⁺ signaling. The structural basis of the gating in IP₃R has been studied by X-ray crystallography and cryo-electron microscopy, focusing on the domain rearrangements triggered by IP₃ binding. Here, we conducted molecular dynamics (MD) simulations of the three N-terminal domains of IP₃R responsible for IP₃ binding (IBC/SD; two domains of the IP₃ binding core, IBCβ and IBCα, and suppressor domain, SD) as a model system to study the initial gating stage. The response upon removal of IP₃ from the IP₃-bound form of IBC/SD was traced in MD trajectories. The two IBC domains showed an immediate response of opening after removal of IP₃, and SD showed a simultaneous opening motion indicating a tight dynamic coupling with IBC. However, when IBC remained in a more closed form, the dynamic coupling broke and SD exhibited a more amplified closing motion independently of IBC. This amplified SD motion was caused by the break of connection between SD and IBCβ at the hinge region, but was suppressed in the native tetrameric state. The analyses using Motion Tree and the linear response theory clarified that in the open form, SD and IBCα moved collectively relative to IBCβ with a response upon IP₃ binding within the linear regime, whereas in the closed form, such collectiveness disappeared. These results suggest that the regulation of dynamics via the domain arrangement and multimerization is requisite for large-scale allosteric communication in IP₃R gating machinery.