The ankyrin-1 complex is a crucial multiprotein assembly that links the spectrin-based cytoskeleton to the plasma membrane, thereby preserving the cellular mechanical integrity. While recent cryo-electron microscopy studies have resolved its high-resolution structure, the dynamic behavior of its key intersubunit interfaces, critical for complex stability and membrane anchoring, remains poorly understood. To address this gap, we conducted multiscale molecular dynamics simulations of the ankyrin-1 complex embedded in an erythrocyte-mimetic lipid bilayer. Using all-atom simulations, we quantified the binding affinities of five key interfaces (AP, PB-I, AB-II, AB-III, and AR) and identified hotspot residues essential for interfacial stability. All interfaces exhibit multiple metastable substates, characterized by dynamic rearrangements of contact networks and interfacial geometry, highlighting the intrinsic structural plasticity of the complex. Coarse-grained simulations further revealed that the complex induces pronounced lipid reorganization and a distinctive "valley"-like membrane deformation, characterized by global membrane convexity coupled with localized inward indentation of the outer leaflet, thereby sculpting a membrane environment that is optimal for stable embedding. Collectively, these findings offer a comprehensive molecular view of the interface dynamics and membrane anchoring mechanism of the ankyrin-1 complex, deepening our understanding of the cytoskeleton-membrane coupling that is essential for cellular function.
Zhang et al. (Thu,) studied this question.