A Mesoscopic Membrane Model for the Investigation of Mechanisms Underlying Caveolae-Mediated Endocytosis

Wednesday, October 19, 2011: 3:51 PM
101 H (Minneapolis Convention Center)
Belinda S. Akpa1, Richard D. Minshall2, Lewis E Wedgewood3 and Ludwig C Nitsche3, (1)Chemical Engineering and Bioengineering, University of Illinois at Chicago, Chicago, IL, (2)Pharmacology and Anesthesiology, University of Illinois at Chicago, Chicago, IL, (3)Chemical Engineering, University of Illinois at Chicago, Chicago, IL

Caveolae, small, flask-shaped invaginations of mammalian plasma membranes, are ubiquitous features of endothelial cells.  They comprise about 15% of the cell volume and account for >95% of the plasmalemmal vesicles within the cells. Caveolae are implicated as essential vesicle carriers mediating endocytosis in endothelial cells. In this work, we report the development of a computational model which can address how changes in caveolin-1 oligomerization and key signaling reactions impact upon membrane invagination, budding, and internalization by (i) controlling the stability of caveolin polymers in the plasma membrane and (ii) their ability to facilitate changes in membrane curvature.

A novel mesoscopic, particulate model is developed for cell membranes in which local directionality (surface normal vector) is extracted from the relative arrangement of isotropic particles rather than being embedded in the more complex (i.e., rod-like or multi-bead) internal structure of lipid particles frequently employed in coarse-grained or atomistic simulations. Based on the normal vector, an anisotropic force law is applied having three parts: (1) A pairwise additive, two-dimensional Lennard-Jones force preserves in-plane cohesion. (2) A normal restoring force penalizes excursions from the plane and maintains a spontaneous curvature, thereby imparting bending elasticity.  (3) An anisotropic Brownian force confers in-plane fluidity.  This approach is contrasted with previous models in the dependence of the normal restoring force on the mean and Gaussian curvatures. 

The membrane model is to be combined with a previously developed model of the Cav-1 protein coat characteristic of caveolae in endothelial cells.  This Brownian dynamics simulation, adapted from polymer kinetic theory, represents the protein chains as bead-spring assemblies and tracks their stochastic motion as forces that are transmitted to the membrane.  By combining Brownian dynamics of Cav-1 oligomers anchored to the membrane with the elastic membrane response, a model of caveolin-mediated membrane deformation will be obtained.

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