Molecular dynamics study of stiffness and rupture of axonal membranes

Abstract

AbstractDiffuse axonal injury (DAI), characterized by widespread damage to axons throughout the brain, represents one of the most devastating and difficult to treat forms of traumatic brain injury. Different theories exist about the mechanism of DAI, among which, one hypothesis states that membrane poration of the axons initiates DAI. To investigate the hypothesis, molecular models of axonal membranes, incorporating 25 different lipids distributed asymmetrically in the leaflets, were developed using a coarse-grain description and simulated using molecular dynamics techniques. Employing a bottom-top approach, the results were coupled with a finite element model representing the axon at the cell level. Different protein concentrations were embedded inside the lipid bilayer to describe the different sub-cellular parts in myelinated and unmyelinated axon. The models were investigated in equilibration and under deformation to characterize the structural and mechanical properties of the membranes and comparisons were made with other subcellular parts, particularly myelin. The results indicate that pore formation in the node-of-Ranvier occurs at a lower rupture strain compared to other axolemma part, whereas myelin poration exhibits the highest rupture strains among the investigated models. The observed rupture strain for the node-of-Ranvier aligns with experimental studies, indicating a threshold for injury at axonal strains exceeding 10-13% depending on the strain rate. The results indicate that the hypothesis suggesting mechanoporation triggers axonal injury cannot be dismissed, as this phenomenon occurs within the threshold of axonal injury.HighlightsDeveloping a realistic molecular model of axolemma based on experimental data about its lipid compositionInvestigating how lipid composition and protein concentration affect the membrane’s structural and mechanical propertiesIdentifying the most vulnerable regions of the axonal membrane