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

Abstract

AbstractBackgroundInteraction of beta-2-glycoprotein I (β2GPI) 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.ObjectivesThis study aims to elucidate the mechanism by which DV ofβ2GPI 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 intoβ2GPI’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 ofβ2GPI by antiphospholipid antibodies.ConclusionThe study advances our understanding of the molecular interactions be-tweenβ2GPI’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.