A hydrophobic surface is essential to inhibit the aggregation of a tau-protein-derived hexapeptide.

This paper seeks to understand how a macrocyclic β-sheet peptide inhibits the aggregation of the tau-protein-derived peptide Ac-VQIVYK-NH2 (AcPHF6). Previous studies established that macrocyclic β-sheet peptide 1 inhibits AcPHF6 aggregation, while the sequence isomer in which the lysine and leucine residues at positions R6 and R7 are swapped has little effect on AcPHF6 aggregation. The current studies find that positions R1, R3, and R7 are especially sensitive to mutations. Reducing hydrophobicity at these positions substantially diminishes inhibition. Although position R5 is not sensitive to mutations that reduce hydrophobicity, it is sensitive to mutations that increase hydrophobicity. Enhanced hydrophobicity at this position substantially enhances inhibition. These studies establish that the hydrophobic surface comprising residues R1, R3, and R7 is crucial to the inhibition process and that the residue R5, which shares this surface, is also important. Collectively, these findings demonstrate that hydrophobic surfaces between β-sheet layers are important in inhibiting amyloid aggregation.