AbstractCa2+/calmodulin-dependent protein kinase II (CaMKII) accounts for up to 2 percent of all brain protein and is essential to memory function. CaMKII activity is known to regulate dynamic shifts in the size and signaling strength of neuronal connections, a process known as synaptic plasticity. Increasingly, computational models are used to explore synaptic plasticity and the mechanisms regulating CaMKII activity. Conventional modeling approaches may exclude biophysical detail due to the impractical number of state combinations that arise when explicitly monitoring the conformational changes, ligand binding, and phosphorylation events that occur on each of the CaMKII holoenzyme’s twelve subunits. To manage the combinatorial explosion without necessitating bias or loss in biological accuracy, we use a specialized syntax in the software MCell to create a rule-based model of the twelve-subunit CaMKII holoenzyme. Here we validate the rule-based model against previous measures of CaMKII activity and investigate molecular mechanisms of CaMKII regulation. Specifically, we explore how Ca2+/CaM-binding may both stabilize CaMKII subunit activation and regulate maintenance of CaMKII autophosphorylation. Noting that Ca2+/CaM and protein phosphatases bind CaMKII at nearby or overlapping sites, we compare model scenarios in which Ca2+/CaM and protein phosphatase do or do not structurally exclude each other’s binding to CaMKII. Our results suggest a functional mechanism for the so-called “CaM trapping” phenomenon, such that Ca2+/CaM structurally excludes phosphatase binding and thereby prolongs CaMKII autophosphorylation. We conclude that structural protection of autophosphorylated CaMKII by Ca2+/CaM may be an important mechanism for regulation of synaptic plasticity.Author summaryIn the hippocampus, the dynamic fluctuation in size and strength of neuronal connections is thought to underlie learning and memory processes. These fluctuations, called synaptic plasticity, are in-part regulated by the protein calcium/calmodulin-dependent kinase II (CaMKII). During synaptic plasticity, CaMKII becomes activated in the presence of calcium ions (Ca2+) and calmodulin (CaM), allowing it to interact enzymatically with downstream binding partners. Interestingly, activated CaMKII can phosphorylate itself, resulting in state changes that allow CaMKII to be functionally active independent of Ca2+/CaM. Phosphorylation of CaMKII at Thr-286/287 has been shown to be a critical component of learning and memory. To explore the molecular mechanisms that regulate the activity of CaMKII holoenzymes, we use a rule-based approach that reduces computational complexity normally associated with representing the wide variety of functional states that a CaMKII holoenzyme can adopt. Using this approach we observe regulatory mechanisms that might be obscured by reductive approaches. Our results newly suggest that CaMKII phosphorylation at Thr-286/287 is stabilized by a mechanism in which CaM structurally excludes phosphatase binding at that site.
Animating Cognitive Models and Architectures: A Rule-Based Approach