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

BackgroundInteraction of beta-2-glycoprotein I ({beta}2GPI) with anionic membranes is crucial in antiphospholipid syndrome (APS), implicating the role of its membrane bind-ing domain, Domain V (DV). The mechanism of DV binding to anionic lipids is not fully understood. ObjectivesThis study aims to elucidate the mechanism by which DV of {beta}2GPI binds to anionic membranes. MethodsWe 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. ResultsThe 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 {beta}2GPIs 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 {beta}2GPI by antiphospholipid antibodies. ConclusionThe study advances our understanding of the molecular interactions be-tween {beta}2GPIs 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.