Physical Interactions Driving the Activation/Inhibition of CaMKII

IGNACIO J. GENERAL

Workshop; Workshop of Molecular Modeling in Drug Discovery and Design; 2021

Calcium/CalmodulinProtein Kinase II (CaMKII) is a protein kinase whose function isregulated by the binding of the Calcium/Calmodulin complex(Ca2+/CaM). It is a major player in the Long TermPotentiation process where it acts as a molecular switch, oscillatingbetween inhibited and active conformations. The mechanism for theswitching is thought to be initiated by Ca2+/CaM binding,which allows the trans-phosphorylation of a subunit of CaMKII by aneighboring kinase, leading to the active state of the system. Acombination of all-atom and coarse-grained MD simulations with freeenergy calculations, led us to reveal an interplay of electrostaticforces exerted by Ca2+/CaM on CaMKII, which initiate theactivation process. The highly electrically charged Ca2+/CaMneutralizes basic regions in the linker domain of CaMKII,facilitating its opening and consequent activation. The emergingpicture of CaMKII’s behavior highlights the preponderance ofelectrostatic interactions, and how the modulation of these forces—byway of Ca2+/CaM or phosphorylation of key sites—governsits conformational transitions. p { margin-bottom: 0.1in; line-height: 120% }