Exploration of inositol 1,4,5-trisphosphate (IP(3)) regulated dynamics of N-terminal domain of IP(3) receptor reveals early phase molecular events during receptor activation

Inositol 1, 4, 5-trisphosphate (IP(3)) binding at the N-terminus (NT) of IP(3) receptor (IP(3)R) allosterically triggers the opening of a Ca(2+)-conducting pore located ~100 Å away from the IP(3)-binding core (IBC). However, the precise mechanism of IP(3) binding and correlated domain dynamics in the NT that are central to the IP(3)R 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(3)-binding, complementing existing suggestions on IP(3)R 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 IP(3)R 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(3). This seems to play a major role in determining the IP(3) 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(3) binding that lead to channel gating.