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Abstract (Expand)

Pathogens use sophisticated adhesion mechanisms to remain attached to the host’s surfaces. A key example of this is the adhesion of erythrocytes infected with Plasmodium, the parasite which causes malaria, to the microvasculature. Remarkably, in the case of pregnancy-associated malaria, the adherence of parasitized erythrocytes to the placenta is enhanced by the shear of the flowing blood, suggesting a catch-bond adhesion mechanism. The adhesion is mediated by a parasite protein called VAR2CSA which anchors such infected erythrocytes to the proteoglycan matrix of the placenta. In this work, by using extensive equilibrium and force-probe molecular dynamics simulations, we elucidate the—so far unknown—molecular mechanism governing the adhesive function of VAR2CSA. We demonstrate that the elongation tension that arises from the shear of the flowing blood opens VAR2CSA into two structurally-intact domains, thereby exposing cryptic sugar binding sites. The orientation of VAR2CSA with respect to the pulling direction as well as strong sugar-protein shearing interactions favor this mode of opening. Accordingly, as the basis for a catch bond, we propose that mechanical forces strengthen the adhesion of infected erythrocytes, by increasing the number of sugar binding sites in VAR2CSA and not the bond lifetime as it would be canonically thought for a catch bond. This constitutes a new intriguing hypothesis which is of high relevance for our understanding of malaria infection and for the design of vaccines. More generally, our results put forward force-induced multivalency of mechano-responsive proteins as a key new concept for pathogen-host interactions.

Authors: Rita Roessner, Nicholas Michelarakis, Frauke Gräter, Camilo Aponte-Santamaría

Date Published: 8th Feb 2024

Publication Type: Journal

Abstract (Expand)

Poly(<i>para</i>-phenylene ethynylene)s, or short PPEs, are a class of conjugated and semi-flexible polymers with a strongly delocalized π electron system and increased chain stiffness. Due to this, PPEs have a wide range of technological applications. Although the material properties of single-chains or mixtures of few PPE chains have been studied in detail, the properties of large assemblies remain to be fully explored. Here, we developed a coarse-grained model for PPEs with the Martini 3 force field to enable computational studies of PPEs in large-scale assembly. We used an optimization geometrical approach to take the shape of the π conjugated backbone into account and also applied an additional angular potential to tune the mechanical bending stiffness of the polymer. Our Martini 3 model reproduces key structural and thermodynamic observables of single PPE chains and mixtures, such as persistence length, density, packing and stacking. We show that chain entanglement increases with the expense of nematic ordering with growing PPE chain length. With the Martini 3 PPE model at hand, we are now able to cover large spatio-temporal scales and thereby to uncover key aspects for the structural organization of PPE bulk systems. The model is also predicted to be of high applicability to investigate out-of-equilibrium behavior of PPEs under mechanical force.

Authors: Matthias Brosz, Nicholas Michelarakis, Uwe H F Bunz, Camilo Aponte-Santamaría, Frauke Gräter

Date Published: 4th May 2022

Publication Type: Journal


hts into the mechanism governing the shear thinning effects observed in Nafion solutions, through the use of non-equilibrium, coarse-grained, molecular dynamic simulations.

Authors: Nicholas Michelarakis, Florian Franz, Konstantinos Gkagkas, Frauke Gräter

Date Published: 24th Nov 2021

Publication Type: Journal

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