This is a taster session of the spatial stochastic modelling software MCell, which is used for modelling biochemical events. In MCell, every molecule is explicitly represented. It can move around in space and change or interact with other molecules according to rules specified by the user. We use an MCell plugin to Blender both to design the model and to visualise simulation results.

We will use MCell to model a simplified version of what happens in neurons when we form memories. When we learn, connections between neurons (synapses) get strengthened. It is said that “neurons that fire together, wire together”. On a molecular level, this strengthening is mediated by molecular changes in the neuron at the receiving end of the synapse (the post-synaptic neuron): When a postsynaptic neuron gets activated, a set of transmembrane receptors called AMPA receptors (AMPARs) become activated and change the electrical properties of the cell. Then, if there is another activation event, another transmembrane receptor, the NMDA receptor (NMDAR) is activated and allows Calcium to enter the cell. Calcium activates a protein called calmodulin, which then activates another protein called CaMKII (this is short for Calcium-/calmodulin-activated kinase II). A kinase is a protein that catalyses the phosphorylation of other proteins. One of the proteins phosphorylated by CaMKII is the AMPA receptor itself. Phopshorylation causes AMPA receptors to be more active and also causes more AMPA receptors to be inserted into the cell membrane at this particular site. So, the next time there is an activation event, there are more receptors to receive it. This is what we mean when we say the synapse is “strengthened”. (This is a simplified explanation, and there are many other molecular interactions in place that serve to fine-tune this system and to ensure that strengthened synapses can remain that way for a long period of time.)

The system we are modelling today is a very simple version of what happens in a synapse upon activation:

Getting started with MCell and CellBlender

This tutorial will assume you have MCell and CellBlender already installed. For instructions on how to do this, see here

Calcium binding to CaMKII

What happens in this reaction? How would you expect the conentrations of CaMKII, Calcium, and active_CaMKII to change over time?

Can you tell which is which? Go to the Molecules tab in order to see what molecule is associated with what colour.

What changes over the course of the simulation? Is this consistent with your expectations?

Where does the Calcium come from?

NMDAR' -> Calcium, + NMDAR'

Forget about the apostrophes and commas for now (if you want to learn more, there is an advanced tutorial here). What happens in this reaction? Why are we using this as a way of representing Calcium moving into the cell?

How much Calcium is there at the start of the simulation? How much is there at the end? How does this affect CaMKII activation?

AMPA receptor activation

How would you write this as a chemical reaction (or set of reactions)?

Is this what you would have done? Does this make sense to you?

What would you expect to be different from the last simulation?

Does this confirm what you expected?

Checking out diffusion

Do you have a suggestion as to how to make it visible?

What happens here?

What do you see?

The Plot thickens

What does the plot show? What’s on the x axis? What’s on the y axis? What colour is what? How does this relate to what you have seen? Looking at the plot, do you notice something that might not be quite right?

Why are there limits? How? How could you model something like that in the MCell model? You might have to add a reaction, or even another molecule.