Simulations of molecules and processes in the synapse

Abstract

Two nanosecond-timescale molecular dynamics simulations of acetylcholinesterase (EC 3.1.1.7) were analyzed: one unliganded, the other complexed with the snake-venom toxin fasciculin 2. These simulation trajectories revealed complex fluctuation of the active site gorge. In both simulations, we observe a two-peaked probability distribution of the gorge width. Comparing the gorge width with the principal components of motion showed that collective motions of many scales contribute to the opening behavior of the gorge. Covariance and correlation results, as displayed in the novel “porcupine plots”, identified the motions of the protein backbone as the gorge opens.

Fasciculin 2 binds to the gorge entrance of acetylcholinesterase with excellent complementarity and many polar and hydrophobic interactions; it appears to sterically block access of ligands to the gorge. When fasciculin is present, the gorge width distribution is altered such that the gorge is more likely to be narrow. Moreover, there are large increases in the opening of alternative passages, namely the side door and the back door. Finally, the catalytic triad arrangement in the acetylcholinesterase active site is disrupted with fasciculin bound. These data support that, in addition to the steric obstruction seen in the crystal structure, fasciculin may inhibit acetylcholinesterase by combined allosteric and dynamical means.

On a larger scale, the general infrastructure for solving the time-dependent diffusion equation using the finite element method has been implemented. Simulations of synaptic transmission were performed using simplified rectilinear models of the neuromuscular junction to demonstrate the effects of synaptic geometries and reactivity parameters. Observations from models representing synapses in fast- and slow-twitch muscles follow the trends of experimental data. One of our models explains the effects of geometry in muscular dystrophy; another demonstrates the capability of our infrastructure to simulate complicated realistic models based on electron microscopy data.