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We developed coarse-grained models of spike proteins in SARS-CoV-2 coronavirus and angiotensin-converting enzyme 2 (ACE2) receptor proteins to study the endocytosis of a whole coronavirus under physiologically relevant spatial and temporal scales. We first conducted all-atom explicit-solvent molecular dynamics simulations of the recently characterized structures of spike and ACE2 proteins. We then established coarse-grained models using the shape-based coarse-graining approach based on the protein crystal structures and extracted the force field parameters from the all-atom simulation trajectories. To further analyze the coarse-grained models, we carried out normal mode analysis of the coarse-grained models to refine the force field parameters by matching the fluctuations of the internal coordinates with the original all-atom simulations. Finally, we demonstrated the capability of these coarse-grained models by simulating the endocytosis of a whole coronavirus through the host cell membrane. We embedded the coarse-grained models of spikes on the surface of the virus envelope and anchored ACE2 receptors on the host cell membrane, which is modeled using a one-particle-thick lipid bilayer model. The coarse-grained simulations show the spike proteins adopt bent configurations due to their unique flexibility during their interaction with the ACE2 receptors, which makes it easier for them to attach to the host cell membrane than rigid spikes. 

Abstract The final stages of mammalian erythropoiesis involve enucleation, membrane and proteome remodeling, and organelle clearance. Concomitantly, the erythroid membrane skeleton establishes a unique pseudohexagonal spectrin meshwork that is connected to the membrane through junctional complexes. The mechanism and signaling pathways involved in the coordination of these processes are unclear. The results of our study revealed an unexpected role of the membrane skeleton in the modulation of proteome remodeling and organelle clearance during the final stages of erythropoiesis. We found that diaphanous-related formin mDia2 is a master regulator of the integrity of the membrane skeleton through polymerization of actin protofilament in the junctional complex. The mDia2-deficient terminal erythroid cell contained a disorganized and rigid membrane skeleton that was ineffective in detaching the extruded nucleus. In addition, the disrupted skeleton failed to activate the endosomal sorting complex required for transport-III (ESCRT-III) complex, which led to a global defect in proteome remodeling, endolysosomal trafficking, and autophagic organelle clearance. Chmp5, a component of the ESCRT-III complex, is regulated by mDia2-dependent activation of the serum response factor and is essential for membrane remodeling and autophagosome-lysosome fusion. Mice with loss of Chmp5 in hematopoietic cells in vivo resembled the phenotypes in mDia2-knockout mice. Furthermore, overexpression of Chmp5 in mDia2-deficient hematopoietic stem and progenitor cells significantly restored terminal erythropoiesis in vivo. These findings reveal a formin-regulated signaling pathway that connects the membrane skeleton to proteome remodeling, enucleation, and organelle clearance during terminal erythropoiesis. 

Computational modeling and simulations can tackle a broad range of morphological, mechanical, and rheological problems relevant to blood and blood cells. Here, we review some continuum-based and particle-based computational approaches towards the modeling of healthy and diseased red blood cells (RBCs) with focus on the most recent contributions, including the three-level multiscale RBC model coupled with the boundary integral method of surrounding flows and two-component RBC models with explicit descriptions of lipid bilayer, cytoskeleton, and transmembrane proteins.