From Atoms to Neuronal Spikes: A Multi-Scale Simulation Framework.

Understanding how molecular events in ion channels impact neuronal excitability, as derived from the calculation of the time course of the membrane potentials, can help elucidate the mechanisms of neurological disease-linked mutations and support neuroactive drug design. Here, we propose a multi-scale simulation approach which couples molecular simulations with neuronal simulations to predict the variations in membrane potential and neural spikes. We illustrate this through two examples. First, molecular dynamics simulations predict changes in current and conductance through the AMPAR neuroreceptor when transitioning from the wild-type protein to certain disease-associated variants. The results of these simulations inform morphologically detailed models of cortical pyramidal neurons, which are simulated using the Arbor framework to determine neural spike activity. Based on these multiscale simulations, we suggest that disease associated AMPAR variants may significantly impact neuronal excitability. In the second example, the Arbor model is coupled with coarse-grained Monte Carlo gating simulations of voltage-gated (K