Exploration of inositol 1,4,5-trisphosphate (IP3) regulated dynamics of N-terminal domain of IP3 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.