Current views of the role of b-amyloid (Ab) peptide fibrils range\ud from regarding them as the cause of Alzheimer’s pathology to\ud having a protective function. In the last few years, it has also\ud been suggested that soluble oligomers might be the most important\ud toxic species. In all cases, the study of the conformational\ud properties of Ab peptides in soluble form constitutes a basic approach\ud to the design of molecules with “antiamyloid” activity. We\ud have experimentally investigated the conformational path that\ud can lead the Ab-(1-42) peptide from the native state, which is\ud represented by an a helixembedd ed in the membrane, to the\ud final state in the amyloid fibrils, which is characterized by bsheet\ud structures. The conformational steps were monitored by\ud using CD and NMR spectroscopy in media of varying polarities.\ud This was achieved by changing the composition of water and\ud hexafluoroisopropanol (HFIP). In the presence of HFIP, b conformations\ud can be observed in solutions that have very high water\ud content (up to 99% water; v/v). These can be turned back to a\ud helices simply by adding the appropriate amount of HFIP. The\ud transition of Ab-(1-42) from a to b conformations occurs when\ud the amount of water is higher than 80% (v/v). The NMR structure\ud solved in HFIP/H2O with high water content showed that, on\ud going from very apolar to polar environments, the long N-terminal\ud helixis essentially retained, whereas the shorter C-terminal\ud helixis lost. The complete conformational path was investigated\ud in detail with the aid of molecular-dynamics simulations in explicit\ud solvent, which led to the localization of residues that might\ud seed b conformations. The structures obtained might help to find\ud regions that are more affected by environmental conditions in\ud vivo. This could in turn aid the design of molecules able to inhibit\ud fibril deposition or revert oligomerization processes
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