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Previous studies found that Vitamin E (VE) could recruit protein kinase B (Akt1) to the membrane by targeting its unconventional lipid-binding site, which led to the dephosphorylation of Akt1 at Ser473, eventually deactivating the enzyme. A series of VE-like compounds with varying types and lengths of the linker groups are designed to study the VE-driven membrane recruitment of Akt1 using a combined molecular docking and molecular dynamics (MD) simulation approach. We find that the linker groups with only one methylene linker and multiple hydrogen bond donors are optimal for achieving a balance between binding to the protein and partitioning into the membrane to form a stable protein-ligand-membrane ternary complex. These polar linkers are found to form stable hydrogen bonds with the lipid head groups during the MD simulations, which turns out critical for ensuring that the chromanol ring of the VE-like compounds resides above the membrane surface to fully engage in the protein. Our results reveal the molecular determinants of the linker groups for VE derivatives' ability to anchor Akt1 to the membrane. These findings will facilitate the design of membrane interfacial compounds to recruit specific proteins to the membrane to modulate the protein function. • Vitamin E derivatives for Akt1 inactivation. • Computational design of membrane interfacial binders. • Molecular determinants of Vitamin E derivatives for membrane recruitment. [ABSTRACT FROM AUTHOR]