Inhibition of Aggregation in B-Sheet Model Peptide by PPII Helix Capping

Abstract

A 12mer peptide (Beta, SWTVEGNKYTYK-NH2) was designed based on the Trpzip model. Beta can form an aggregate with fibril like morphology imaged by TEM. The secondary structure of the fibril was characterized to be anti-parallel β-sheets by FT-IR spectra. VCD (Vibrational Circular Dichroism) spectrum demonstrated the supramolecular chirality of the fibril and UV-CD spectrum of this peptide confirmed the tertiary contact between aromatic residues in the sequence. Upon mutation with an added PPII helix inducing combo to the C-terminal of this peptide, a new peptide BP (SWTVEGNKYTYKNGAPPPK-NH2) was synthesized. BP did not enhance ThT fluorescence, its secondary structure was characterized to be unordered by UV-CD and FT-IR spectra. Further FRET analysis with a dansylated version of BP shows that the end to end distance is consistent with the proline mutations disrupting the aromatic contacts and thus stabilized the unordered conformation. In contrast, 1:1 ratio mixture of a 9mer PPII conformation peptide and Beta did not change the aggregation behavior of Beta. This study points out that sequence mutation is crucial in order to change the propensity of aggregation in peptides.