Discussion
Cut and pasted from the Introduction. The following should be compared and contrasted with the results we produced: The Wetzel group performed scanning proline and alanine mutagenesis studies of Aβ40 24, 25. Residues whose substitution with proline changed peptide assembly, residues 15-21, 24-28, and 31-36, were determined to be regions that form β-sheets. The remaining residues, for which substitution had no effect, were found to be in disordered, loop, or turn regions in Aβ40 24. Alanine substitutions between 15-36 led to slower fibril elongation compared to wild-type Aβ40. The authors speculated that these changes in assembly kinetics resulted from differences in hydrophobic packing 25. Other studies have shown that the Aβ N-terminus is particularly important in controlling aggregation kinetics of Aβ40, whereas the C-terminus is most important in controlling Aβ42 aggregation kinetics 26-28. The central hydrophobic cluster (CHC), Aβ(17-21), appears to play an important role in maintaining the ability of Aβ to form plaques and in regulating aggregation propensity 29. The Aβ(21-30) turn region has been reported to nucleate monomer folding, a key step in the Aβ assembly process 27.
The metastable and heterogeneous nature of Aβ oligomers 38 has made it difficult to obtain detailed structural and functional characterization of Aβ40 and Aβ42 oligomers 39 . However, to develop knowledge-based drug therapies for AD, the structure and function of Aβ must be well understood. This study focused on understanding the mechanisms behind Aβ monomer folding and assembly by identifying individual amino acids that affect Aβ folding and assembly dynamics.