Study of Protein Diffusion in Defective Erythrocyte Membrane

Abstract

In the hemolytic disorders of hereditary spherocytosis (HS) and hereditary elliptocytosis (HE), the red blood cells (RBCs) are abnormal. In HS, membrane proteins that facilitate the vertical interactions between the lipid bilayer and the spectrin cytoskeleton are defective, resulting in RBC membrane loss and the spherical shape of the erythrocytes. In HE, membrane proteins that support the horizontal interactions within the spectrin cytoskeleton are defective, resulting in loss of the elasticity of the spectrin network and the elliptic shape of the erythrocytes. Several attempts have been made to experimentally correlate the severity of the disease in each case with higher diffusivity of band-3 proteins located in the RBC membrane. However, the experimental results are inconclusive. To better understand them, input from simulations is needed. Because of the complexity of the system however, the implementation of atomistic simulations is not feasible. In this work, we introduce a two-component, coarse-grain molecular dynamics erythrocyte membrane model that simulates explicitly the phospholipid bilayer, membrane proteins, and the cytoskeleton by coarse-grain particles. The particles represent the actin junctions, spectrin, glycophorin, immobile band-3, mobile band-3 and aggregation of lipids. The proposed model allows us to study the diffusion of band-3 particles in the healthy RBC membrane and in HS and HE RBC membranes. We can observe the hop diffusion of band-3 proteins between the corrals formed by the cytoskeleton. In addition, we measure the band-3 diffusion in the membrane with proteins defects in the vertical and horizontal interactions, respectively. The measured diffusion coefficients demonstrated that spectrin content is the major determinant of the lateral diffusion of band-3. Direct comparison with experimental results is very promising.