Exploration of inositol 1,4,5-trisphosphate (IP) regulated dynamics of N-terminal domain of IP receptor reveals early phase molecular events during receptor activation.

Inositol 1, 4, 5-trisphosphate (IP) binding at the N-terminus (NT) of IP receptor (IPR) allosterically triggers the opening of a Ca-conducting pore located ~100 Å away from the IP-binding core (IBC). However, the precise mechanism of IP binding and correlated domain dynamics in the NT that are central to the IPR activation, remains unknown. Our all-atom molecular dynamics (MD) simulations recapitulate the characteristic twist motion of the suppressor domain (SD) and reveal correlated 'clam closure' dynamics of IBC with IP-binding, complementing existing suggestions on IPR activation mechanism. Our study further reveals the existence of inter-domain dynamic correlation in the NT and establishes the SD to be critical for the conformational dynamics of IBC. Also, a tripartite interaction involving Glu283-Arg54-Asp444 at the SD - IBC interface seemed critical for IPR activation. Intriguingly, during the sub-microsecond long simulation, we observed Arg269 undergoing an SD-dependent flipping of hydrogen bonding between the first and fifth phosphate groups of IP. This seems to play a major role in determining the IP binding affinity of IBC in the presence/absence of the SD. Our study thus provides atomistic details of early molecular events occurring within the NT during and following IP binding that lead to channel gating.