A particle-based computational model to analyse remodelling of the red blood cell cytoskeleton during malaria infections

Abstract

Red blood cells can withstand the harsh mechanical conditions in the vasculature only because the bending rigidity of their plasma membrane is complemented by the shear elasticity of the underlying spectrin-actin network. During an infection by the malaria parasite Plasmodium falciparum, the parasite mines host actin from the junctional complexes and establishes a system of adhesive knobs, whose main structural component is the knob-associated histidine rich protein (KAHRP) secreted by the parasite. Here we aim at a mechanistic understanding of this dramatic transformation process. We have developed a particle-based computational model for the cytoskeleton of red blood cells and simulated it with Brownian dynamics to predict the mechanical changes resulting from actin mining and KAHRP-clustering. Our simulations include the three-dimensional conformations of the semi-flexible spectrin chains, the capping of the actin protofilaments and several established binding sites for KAHRP. For the healthy red blood cell, we find that incorporation of actin protofilaments leads to two regimes in the shear response. Actin mining decreases the shear modulus, but knob formation increases it. We show that dynamical changes in KAHRP binding affinities can explain the experimentally observed relocalization of KAHRP from ankyrin to actin complexes and demonstrate good qualitative agreement with experiments by measuring pair cross-correlations both in the computer simulations and in super-resolution imaging experiments.

Dynamic mechanisms for membrane skeleton transitions

“…To simulate such a dynamic meshwork, we chose a simplified representation of spectrin bundles as Hookean springs. Spectrin bundles are usually represented using a Worm Like Chain (WLC) model (25,28,45) to account for thermal fluctuations of polymers (46), or interpolation of the WLC (24,26,(47)(48)(49)(50) proposed by (51,52), which avoids the collapse of the spectrin bundle under compression and bounds it under expansion while behaving like an ideal spring at the minimum (47). These representations of spectrin bundles are highly non-linear and require significant computational power.…”

“…Thus, a Hookean spring representation of the spectrin bundles is well-suited for our investigation. This mesoscopic depiction of the membrane skeleton, which omits its molecular details given in other models ( 25, 30, 31 ), allows us to examine the overall configuration changes due to the induced stresses. Importantly, we chose this mesoscopic model because we are interested in the effects of dynamically adding and removing, either randomly or due to applied forces, the skeleton components embedded in a membrane.…”

“…Following (11), instead of focusing on exact values for the different model parameters, which are difficult to obtain experimentally and may diverge for different types of cells, we focused on values that allow us to qualitatively represent 4 the meshwork dynamics. Thus, unlike previous modeling efforts that only focus on one type of cell (24)(25)(26)(27)(28)(29)(30)(31), our model is general. The model parameters are provided in Table 1.…”

Mechanism and Effects of Cellular Creep in a Microfluidic Filter

“…21 In this study, this mainly refers to the viscosity of solid particles, which can be described by two physical parameters: the shear modulus (SM) and the relaxation time (RT). 22,23 Viscoelastic microparticles were found to experience a weird continuous morphologic change under a constant loading, which is referred to as viscoelastic creep. This will not only result in a longer processing time but also probably lead to a low recovery rate and poor detection precision.…”

“…Additionally, the mechanics of different viscous cells will result in various dynamic performances in microfluidic applications. − The transport of flowing cells into the confined microscale structure will induce clogging and trapping, which is related to the surround fluid dynamics and soft matter characteristics of the cell . In this study, this mainly refers to the viscosity of solid particles, which can be described by two physical parameters: the shear modulus (SM) and the relaxation time (RT). , Viscoelastic microparticles were found to experience a weird continuous morphologic change under a constant loading, which is referred to as viscoelastic creep. This will not only result in a longer processing time but also probably lead to a low recovery rate and poor detection precision. − …”