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