Biophysical Society Thematic Meeting | Hamburg 2022

Biophysics at the Dawn of Exascale Computers

Poster Abstracts

38-POS Board 38 AVIDITY OF THE MALARIA ADHESIN VAR2CSA IS MECHANO-CONTROLLED BY EXPOSURE OF A SECOND CRYPTIC CSA SUGAR BINDING SITE Nicholas Michelarakis 1 ; Rita Rössner 1 ; Frauke Gräter 1,2 ; Camilo Aponte-Santamaría 1 ; 1 Heidelberg Institute for Theoretical Studies, Molecular Biomechanics Group, Heidelberg, Germany 2 Heidelberg University , Interdisciplinary Center for Scientific Computing, Heidelberg, Germany Plasmodium falciparum (Pf) is responsible for the most lethal form of malaria. VAR2CSA is the adhesin protein expressed by the parasite at the membrane of the infected erythrocytes for attachment on the placenta, leading to pregnancy-associated malaria. Accordingly, this protein is a target of vaccines against placental-malaria. VAR2CSA is a large, 350 kDa multidomain protein composed of nine extracellular domains, a transmembrane helix, and an intracellular domain. Chondroitin Sulphate A (CSA) serves as the substrate and anchor point of VAR2CSA. Shear flow, as the one occurring in blood, has been shown to enhance VAR2CSA adhesion on the CSA-matrix. However, the underlying molecular mechanism by which mechanical force influences the adhesivity of this protein still remains elusive. Here, we shed light on this question through the use of million-atom equilibrium and force-probe molecular dynamic simulations, with a cumulative sampling time of more than 2.5 μs. We subjected the VAR2CSA protein -CSA sugar complex to a force mimicking the elongational tension arising from the shear of the flowing blood. We show that upon this force exertion, the CSA sugar chain dissociates from the protein, but before that, the VAR2CSA protein undergoes a large opening conformational transition, exposing a secondary CSA binding site. Molecular docking followed by extensive equilibrium molecular dynamics relaxation suggest that a dodecameric CSA molecule can stably accommodate to the force-exposed binding site. Our results thus suggest that mechanical force increases the avidity of VAR2CSA by uncovering a secondary cryptic CSA binding site. The mechanism provided here paves the way to understanding the molecular mechanism governing the shear enhanced VAR2CSA-CSA interaction. It highlights the mechano-enhanced protein- sugar avidity employed by Pf during malaria-infected erythrocyte adhesion.

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