Activación/Inhibición de CaMKII: Interacciones físicas

IGNACIO J. GENERAL

Simposio; I SIMPOSIO INTERNACIONAL DE MODELADO BIOMOLECULAR Y BIOINFORMÁTICA; 2021

Calcium/Calmodulin Protein Kinase II (CaMKII) is a protein kinase whose function is regulated by the binding of the Calcium/Calmodulin complex (Ca2+/CaM). It is a major player in the Long Term Potentiation process where it acts as a molecular switch, oscillating between inhibited and active conformations. The mechanism for the switching is thought to be initiated by Ca2+/CaM binding,which allows the trans-phosphorylation of a subunit of CaMKII by a neighboring kinase, leading to the active state of the system. A combination of all-atom and coarse-grained MD simulations with free energy calculations, led us to reveal an interplay of electrostatic forces exerted by Ca2+/CaM on CaMKII, which initiate the activation process. The highly electrically charged Ca2+/CaM neutralizes basic regions in the linker domain of CaMKII, facilitating its opening and consequent activation. The emerging picture of CaMKII's behavior highlights the preponderance of electrostatic interactions, and how the modulation of these forces, by way of Ca2+/CaM or phosphorylation of key sites, governs its conformational transitions.