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The β ‐sheet breakers and π‐stacking
Author(s) -
Jarmuła Adam,
Stępkowski Dariusz
Publication year - 2013
Publication title -
journal of peptide science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.475
H-Index - 66
eISSN - 1099-1387
pISSN - 1075-2617
DOI - 10.1002/psc.2506
Subject(s) - conformational isomerism , fibril , chemistry , peptide , stacking , amyloid (mycology) , beta sheet , biophysics , stereochemistry , fibrillation , biochemistry , molecule , biology , organic chemistry , medicine , inorganic chemistry , cardiology , atrial fibrillation
Fibrillation of β ‐amyloid is recognized as a key process leading to the development of Alzheimer's disease. Small peptides called β ‐sheet breakers were found to inhibit the process of β ‐amyloid fibrillation and to dissolve amyloid fibrils in vitro , in vivo , and in cell culture studies [1,2]. The mechanism by which peptide inhibition takes place remains elusive and a detailed model needs to be established. Here, we present new insights into the possible role of consecutive Phe residues, present in the structure of β ‐sheet breakers, supported by the results obtained by means of MD simulations. We performed a 30‐ns MD of two β ‐sheet breakers: iAβ5 (LPFFD) and iAβ6 (LPFFFD) which have two and three consecutive Phe residues, respectively. We have found that Phe rings in these peptides tend to form stacked conformations. For one of the peptides – iAβ6 – the calculated electrostatic contribution to free energy of one of the conformers with three rings stacked (c2) is significantly lower than that corresponding to the unstacked one (c1), two rings stacked (c0) and second conformer with three rings stacked (c3). This may favor the interaction of the c2 conformer with the target on amyloid fibril. We hypothesize that the mechanism of inhibition of amyloidogenesis by β ‐sheet breaker involves competition among π‐stacked Phe residues of the inhibitor and π‐stacking within the β ‐amyloid fibril. iAβ6 may be a promising candidate for a lead compound of amyloidogenesis inhibitors. Copyright © 2013 European Peptide Society and John Wiley & Sons, Ltd.