Redesigning the Alzheimer's Risk Protein for Lipid Interfaces

Apolipoprotein E does most of its pathologically relevant work at lipid interfaces, and its E4 variant is the strongest common genetic risk factor for late-onset Alzheimer's disease. Design efforts have targeted its receptor binding, interdomain geometry or abundance, but not the lipid affinity of its N-terminal bundle.

In our new manuscript, we applied the reverse-QTY code to that bundle. Twenty-two substitutions across 14% of the segment shifted it from hydrophilic to hydrophobic while leaving the fold intact, with a mean Cα RMSD of 0.81 Å against the native structure across five AlphaFold3 models. In all-atom molecular dynamics the variant stays folded in a neuronal bilayer and thins it locally by 10.9 Å.

Preprint: https://doi.org/10.64898/2026.09.25.754306

Code and data: https://github.com/karagol-taner/apoe-reverse-qty