Membrane Geometry Reveals Strengths and Limitations of AlphaFold-Predicted Transmembrane Protein Complexes

AlphaFold-Multimer predicts 189,469 high-confidence transmembrane protein complexes, with 95.4% of 125,657 evaluable multi-helix TM-TM cases matching expected 15–35 Å hydrophobic thickness.

• Why it matters: Confidence scores alone can miss assemblies that violate lipid-bilayer constraints, especially for transmembrane interactions where geometry and membrane placement restrict plausible complexes.
• What they did: The authors evaluated membrane compatibility across AlphaFold Protein Structure Database predictions, then tested whether AlphaFold3 (AF3) improves assembly validity using SERCA-phospholamban and norepinephrine transporter cases plus a 173-target cholesterol benchmark.
• The result: Even with favourable confidence, some complexes show membrane-position or protomer-orientation inconsistencies, AF3 recovered SERCA-phospholamban but not the cholesterol-mediated norepinephrine transporter homodimer, and cholesterol-binding poses were limited, especially for targets released after the AF3 training cutoff.

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