Atomistic Characterization of Beta-2-Glycoprotein I Domain V Interaction with Anionic Membranes

Interaction of beta-2-glycoprotein I ( β ₂ GPI) with anionic membranes is crucial in antiphospholipid syndrome (APS), implicating the role of it's membrane bind-ing domain, Domain V (DV). The mechanism of DV binding to anionic lipids is not fully understood.

This study aims to elucidate the mechanism by which DV of β ₂ GPI binds to anionic membranes.

We utilized molecular dynamics (MD) simulations to investigate the struc-tural basis of anionic lipid recognition by DV. To corroborate the membrane-binding mode identified in the HMMM simulations, we conducted additional simulations using a full mem-brane model.

The study identified critical regions in DV, namely the lysine-rich loop and the hydrophobic loop, 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 β ₂ GPI's membrane interaction. Simulations revealed two 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 β ₂ GPI by antiphospholipid antibodies.

The study advances our understanding of the molecular interactions be-tween β ₂ GPI's DV and anionic membranes, crucial for APS pathogenesis. It highlights the importance of specific regions in DV for membrane binding and reveals a predominant bind-ing mode. These findings have significant implications for APS diagnostics and therapeutics, offering a deeper insight into the molecular basis of the syndrome.