INSTITUTO DE CIENCIAS FISICAS
Unidad Ejecutora - UE
Physical Interactions Driving the Activation/Inhibition of Calcium/Calmodulin Dependent Protein Kinase II
IGNACIO J. GENERAL; PANTANO, SERGIO; ELIANA K. ASCIUTTO
JOURNAL OF MOLECULAR GRAPHICS & MODELLING.
ELSEVIER SCIENCE INC
Lugar: Amsterdam; Año: 2021
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, which are modulated by the presence of Ca2+/CaM and the phosphorylation of key sites.