Date of Completion

4-15-2019

Embargo Period

4-15-2019

Keywords

coarse-grain molecular dynamics; axon plasma membrane; membrane protein diffusion; long-range interaction

Major Advisor

George Lykotrafitis

Associate Advisor

Anastasios V. Tzingounis

Associate Advisor

David M. Pierce

Associate Advisor

Julian Norato

Associate Advisor

Ying Li

Field of Study

Mechanical Engineering

Degree

Doctor of Philosophy

Open Access

Open Access

Abstract

Here, we used the coarse-grain molecular dynamics (CGMD) method to establish a simulation model for the axon plasma membrane (APM) that was then used to study the mechanical properties of the APM and to investigate how the axon plasma membrane skeleton (APMS) affects diffusion of membrane proteins in the axon. Super-resolution microscopy has illustrated that the APMS consists of periodic actin ring-like structures along its length connected by spectrin tetramers and anchored to the lipid bilayer via ankyrin. Based on these experimental results, we developed a CGMD model for the APMS. In particular, the model comprises representations of periodic actin rings, spectrin tetramers, ankyrin, and ankyrin associated sodium channels. The model was validated using atomic force microscopy experimental results, which showed that axons are almost ~6 fold stiffer than the soma and ~2 fold stiffer than dendrites. Using the APMS model, we demonstrated that because the spectrin filaments are under tension, the thermal motion of the actin-associated ankyrin particles is minimal. In addition, we showed that any axonal injuries causing laceration of spectrin filaments will likely lead to a permanent disruption of the membrane skeleton due to the inability of spectrin filaments to spontaneously form their initial under-tension configuration. Then, we extended the APMS model by adding a representation of the lipid bilayer to investigate the effect of the APMS on the diffusion of APM proteins. To reconcile the experimental observations, which show restricted diffusion of integral monotopic proteins (IMPs) of the outer leaflet, with our simulations, we conjectured the existence of actin-anchored proteins that form a fence restricting the longitudinal diffusion of IMPs of the outer leaflet. Our simulations also revealed that spectrin filaments could impede transverse diffusion in the inner leaflet of the axon and in some conditions modify diffusion from normal to abnormal. Finally, we introduced the Barnes-Hut tree algorithm to simulate the long-range potential with both open and periodic boundary conditions. In particular, we simulated the electrostatic potential between particles and validated the simulation method by measuring the electric field of an infinite plane and the Rayleigh-Taylor instability in the presence of the electric charges.

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