Insight into the Stability of Cross-β Amyloid Fibril from VEALYL Short Peptide with Molecular Dynamics Simulation

Amyloid fibrils are found in many fatal neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, type II diabetes, and prion disease. The VEALYL short peptide from insulin has been confirmed to aggregate amyloid-like fibrils. However, the aggregation mechanism of amyloid fibril is poorly understood. Here, we utilized molecular dynamics simulation to analyse the stability of VEALYL hexamer. The statistical results indicate that hydrophobic residues play key roles in stabilizing VEALYL hexamer. Single point and two linkage mutants confirmed that Val1, Leu4, and Tyr5 of VEALYL are key residues. The consistency of the results for the VEALYL oligomer suggests that the intermediate states might be trimer (3-0) and pentamer(3-2). These results can help us to obtain an insight into the aggregation mechanism of amyloid fibril. These methods can be used to study the stability of amyloid fibril from other short peptides

Spectroscopic detection of pseudo-turns in homodetic cyclic penta- and hexapeptides comprising beta-homoproline

Malesevic M, Majer Z, Vass E, et al. Spectroscopic detection of pseudo-turns in homodetic cyclic penta- and hexapeptides comprising beta-homoproline. INTERNATIONAL JOURNAL OF PEPTIDE RESEARCH AND THERAPEUTICS. 2006;12(2):165-177.beta-Amino acids with side chains at C-2 and/or at C-3 are of growing interest in drug design, as they may induce astonishing and unusual peptide conformations. Therefore it is of eminent importance to gather information on the consequences of beta-amino acid incorporation on the three-dimensional structure of a peptide. This paper describes the synthesis and conformational analysis of cyclic penta- and hexapeptides comprising either (S)-Pro or (S)-beta-Hpro. The conformational influence of the beta-homoproline building block was analyzed by the combined application of CD, FT-IR and NMR. While the CD spectra of the proline containing peptides indicate the presence of inverse gamma-turns and beta II-turns, the CD spectra of the beta-homoamino acid analogs are dominated by an unprecedented negative band near 205 nm associated with a pseudo-beta-turn (Psi beta) or pseudo-gamma-turn (Psi gamma). These results were confirmed by FT-IR spectroscopy, which also indicates the formation of two internal hydrogen bonds in the cyclic peptides containing the beta-homoproline. The conformations of the beta-homoproline containing pentapeptides were additionally determined by NMR in combination with MD simulations in two different solvents. The conformation in trifluoroethanol (TFE) is characterized by a bifurcated hydrogen bond stabilizing a pseudo-gamma-turn with beta-homoproline in the central position, nested with a pseudo-beta-turn with beta-homoproline in the i + l position. The combined CD/FT-IR studies clearly show that the replacement of proline by beta-homoproline gives rise to a more flexible peptide backbone, and CD spectroscopy hints towards the presence of pseudo-beta- or pseudo-gamma-turns