Activation of CaMKII: all-atom and coarse-grained molecular dynamics study

IGNACIO J. GENERAL; IVET BAHAR

Conferencia; Gordon Research Conference in Biopolymers; 2014

Calcium/Calmodulin dependent kinase II (CaMKII) is a protein kinase whose function is regulated by the binding of the Calcium/Calmodulin complex (CaM). The complex has a strong influence in Long Term Potentiation (LTP)?the enhancement and strengthening of active synapses?where it acts as a molecular switch, oscillating between an inhibited and an active conformation. The mechanism for the switching is thought to be determined by CaM binding, which allows the trans-phosphorylation of a subunit by a neighboring kinase; this leads to the active state of the system, where its two subdomains, hub and kinase, remain in an undocked conformation.Here we study the alternation between this undocked (active) and docked (inhibited) states, using all-atom and coarse-grain MD simulations. We observe that, once opened, neighboring subunits show stable inter-subunit approaches of kinases to threonines in the linker connecting the hub to the kinase, favoring threonine transphosphorylation. Once a subunit is phosphorylated, its tendency to get back to the inhibited conformation is reduced; thus, its tendency to stay in the active conformation, with its kinase relatively free from the hub domain, is strengthened. This appears to be the right conformation in order to proceed to phosphorylate AMPA receptors, in the initial step of the process of LTP.