One-particle-thick, Solvent-free, Course-grained Model for Biological and Biomimetic Fluid Membranes

Biological membranes are involved in numerous intriguing biophysical and biological cellular phenomena of different length scales, ranging from nanoscale raft formation, vesiculation, to microscale shape transformations. With extended length and time scales as compared to atomistic simulations, solvent-free coarse-grained membrane models have been exploited in mesoscopic membrane simulations. In this study, we present a one-particle-thick fluid membrane model, where each particle represents a cluster of lipid molecules. The model features an anisotropic interparticle pair potential with the interaction strength weighed by the relative particle orientations. With the anisotropic pair potential, particles can robustly self-assemble into fluid membranes with experimentally relevant bending rigidity. Despite its simple mathematical form, the model is highly tunable. Three potential parameters separately and effectively control diffusivity, bending rigidity, and spontaneous curvature of the model membrane. As demonstrated by selected examples, our model can naturally simulate dynamics of phase separation in multicomponent membranes and the topological change of fluid vesicles

Modeling of the axon plasma membrane structure and its effects on protein diffusion.

The axon plasma membrane consists of the membrane skeleton, which comprises ring-like actin filaments connected to each other by spectrin tetramers, and the lipid bilayer, which is tethered to the skeleton via, at least, ankyrin. Currently it is unknown whether this unique axon plasma membrane skeleton (APMS) sets the diffusion rules of lipids and proteins in the axon. To answer this question, we developed a coarse-grain molecular dynamics model for the axon that includes the APMS, the phospholipid bilayer, transmembrane proteins (TMPs), and integral monotopic proteins (IMPs) in both the inner and outer lipid layers. We first showed that actin rings limit the longitudinal diffusion of TMPs and the IMPs of the inner leaflet but not of the IMPs of the outer leaflet. To reconcile the experimental observations, which show restricted diffusion of IMPs of the outer leaflet, with our simulations, we conjectured the existence of actin-anchored proteins that form a fence which restricts the longitudinal diffusion of IMPs of the outer leaflet. We also showed that spectrin filaments could modify transverse diffusion of TMPs and IMPs of the inner leaflet, depending on the strength of the association between lipids and spectrin. For instance, in areas where spectrin binds to the lipid bilayer, spectrin filaments would restrict diffusion of proteins within the skeleton corrals. In contrast, in areas where spectrin and lipids are not associated, spectrin modifies the diffusion of TMPs and IMPs of the inner leaflet from normal to confined-hop diffusion. Overall, we showed that diffusion of axon plasma membrane proteins is deeply anisotropic, as longitudinal diffusion is of different type than transverse diffusion. Finally, we investigated how accumulation of TMPs affects diffusion of TMPs and IMPs of both the inner and outer leaflets by changing the density of TMPs. We showed that the APMS structure acts as a fence that restricts the diffusion of TMPs and IMPs of the inner leaflet within the membrane skeleton corrals. Our findings provide insight into how the axon skeleton acts as diffusion barrier and maintains neuronal polarity

Valsartan impedes epinephrine-induced ICAM-4 activation on normal, sickle cell trait and sickle cell disease red blood cells.

Abnormal red blood cell (RBC) adhesion to endothelial αvβ3 plays a crucial role in triggering vaso-occlusive episodes in sickle cell disease (SCD). It is known that epinephrine, a β-adrenergic receptor (β-AR) stimulator, increases the RBC surface density of active intercellular adhesion molecule-4 (ICAM-4) which binds to the endothelial αvβ3. It has also been demonstrated that in human embryonic kidney 293 cells, mouse cardiomyocytes, and COS-7 cell lines, the β-adrenergic and renin-angiotensin systems are interrelated and that there is a direct interaction and cross-regulation between β-AR and angiotensin II type 1 receptor (AT1R). Selective blockade of AT1R reciprocally inhibits the downstream signaling of β-ARs, similar to the inhibition observed in the presence of a β-AR-blocker. However, it is not known if this mechanism is active in human RBCs. Here, we studied the effect of valsartan, an AT1R blocker, on the surface density of active ICAM-4 receptors in normal, sickle cell trait, and homozygous sickle RBCs. We applied single molecule force spectroscopy to detect active ICAM-4 receptors on the RBC plasma membrane with and without the presence of valsartan and epinephrine. We found that epinephrine significantly increased whereas valsartan decreased their surface density. Importantly, we found that pretreatment of RBCs with valsartan significantly impeded the activation of ICAM-4 receptors induced by epinephrine. The observed reduced expression of active ICAM-4 receptors on the RBC plasma membrane leads us to conjecture that valsartan may be used as a supporting remedy for the prevention and treatment of vaso-occlusive crisis in SCD