A Minimal Coarse-Grained Molecular Dynamics Model of Axon Plasma Membrane with its Implication on the Diffusion Behavior of Axon Membrane Proteins

Abstract

The axon initial segment (AIS) in the neuron has two crucial functions: maintaining the polarity of neurons and initiation of action potentials. One extraordinary feature of the AIS is the separation of somatodendritic and axonal domains which was confirmed by measuring the trajectory of beads attached to various axonal membrane proteins that there exists a diffusion barrier in the AIS restricting the motion of membrane proteins and lipids. According to the “fences and pickets” model, the periodic cytoskeleton and the highly concentrated transmembrane proteins in the AIS are capable of hindering the diffusion of other proteins and lipids through steric interaction and hydrodynamic friction effect. In this work, we established the first coarse-grained molecular dynamics model of axon plasma membrane which includes both axon membrane skeleton and axonal membranes to investigate the diffusion behavior of membrane proteins and lipids in the AIS from a mechanics aspect. First, we found that transmembrane proteins and proteins in the inner lipid leaflet are confined within the areas between the actin rings. We suspected and proved from the computational model that the size of actin associated protein junctions, which connected to the lipid bilayers may restrict the motion of proteins in the outer leaflet. Then we showed that the spectrin-lipid attraction level will affect the circumferential mobility of membrane proteins. Finally, the highly dense membrane proteins slowed down the motion of all membrane proteins even the lipids. We conclude that actin rings and spectrin filaments restrict the motion of membrane proteins along and around the axon, respectively. However, the main mechanism forming the diffusion barrier in the AIS is the accumulation of concentrated transmembrane proteins.