Coarse-Grained Molecular Dynamics Modeling of Defective Erythrocyte Membrane and Sickle Hemoglobin Fibers

Understanding the complex behavior of the normal and defective red blood cell (RBC) membrane requires the development of detailed computational models. In this work, we show that implementation of coarse-grained molecular dynamics (CGMD) methods can answer fundamental questions related to protein diffusion and membrane loss in erythrocytes. In particular, we first developed a two-component CGMD erythrocyte membrane model comprising the lipid bilayer and an implicitly-represented cytoskeleton. The model reproduced the mechanical properties of the RBC membrane illustrating both the fluidic behavior of the lipid bilayer and the elastic properties of the erythrocyte cytoskeleton. By applying shear deformation, we found that the shear stress was mainly due to the cytoskeleton at low shear strain rates while the viscosity of the lipid bilayer contributed to the resulting shear stress at higher strain rates. Building up on the experience acquired from the model above, we then created a RBC membrane model with explicit representation of the cytoskeleton. In addition to the normal RBC membrane, the model can describe the membrane of defective RBCs from patients with hereditary spherocytosis (HS) and hereditary elliptocytosis (HE) by introducing defects that reduce the connectivity between the lipid bilayer and the cytoskeleton (vertical connectivity) or the connectivity of the cytoskeleton (horizontal connectivity), respectively. The model was then applied in the study of band-3 protein diffusion in the normal RBCs and in the RBCs with membrane protein defects. We showed that the diffusion of band-3 protein is more pronounced in the defective RBCs than normal RBC, particularly in HE RBCs, which is in agreement with experimental observations. Further, the explicit two-component CGMD RBC membrane model was used to simulate vesiculation in the normal and defective RBC membrane induced by the spontaneous curvature of the membrane domain or by compression on the lipid bilayer. We found that the vesicle size depended on the membrane connectivity. Lower vertical or horizontal connectivity caused the generation of larger vesicles than the high connectivity. Finally, we introduced a CGMD model to simulate single hemoglobin S (HbS) fibers as a chain of CG particles. We showed that the proposed model was able to efficiently simulate the mechanical behavior of single and interacting HbS fibers. Simulations of the zippering process between two HbS fibers illustrated that the depletion forces induced by HbS monomers were comparable to direct fiber-fiber interaction via the Van der Waals forces