Atomistic characterization of β2-glycoprotein I domain V interaction with anionic membranes.

Background: Interaction of β-glycoprotein I (βGPI) with anionic membranes is crucial in antiphospholipid syndrome (APS), implicating the role of its membrane-binding domain, domain V (DV). The mechanism of DV binding to anionic lipids is not fully understood.

Objectives: This study aimed to elucidate the molecular details of βGPI DV binding to anionic membranes.

Methods: We utilized molecular dynamics simulations to investigate the structural basis of anionic lipid recognition by DV. To corroborate the membrane-binding mode identified in the highly mobile membrane mimetic simulations, we conducted additional simulations using a full membrane model.

Results: The study identified critical regions in DV, namely the lysine-rich loop and the hydrophobic loop, which are essential for membrane association via electrostatic and hydrophobic interactions, respectively. A novel lysine pair contributing to membrane binding was also discovered, providing new insights into βGPI's membrane interaction. Simulations revealed 2 distinct binding modes of DV to the membrane, with mode 1 characterized by the insertion of the hydrophobic loop into the lipid bilayer, suggesting a dominant mechanism for membrane association. This interaction is pivotal for the pathogenesis of APS, as it facilitates the recognition of βGPI by antiphospholipid antibodies.

Conclusion: The study advances our understanding of the molecular interactions between βGPI's DV and anionic membranes, which are crucial for APS pathogenesis. It highlights the importance of specific regions in DV for membrane binding and reveals a predominant binding mode. These findings have significant implications for APS diagnostics and therapeutics, offering a deeper insight into the molecular basis of the syndrome.