A small molecule stabilises the disordered native state of the Alzheimer's Aβ peptide [article]

Thomas Löhr, Kai Kohlhoff, Gabriella T. Heller, Carlo Camilloni, Michele Vendruscolo
2021 bioRxiv   pre-print
AbstractThe stabilisation of native states of proteins is a powerful drug discovery strategy. It is still unclear, however, whether this approach can be applied to intrinsically disordered proteins. Here we report a small molecule that stabilises the native state of the Aβ42 peptide, an intrinsically disordered protein fragment associated with Alzheimer's disease. We show that this stabilisation takes place by a dynamic binding mechanism, in which both the small molecule and the Aβ42 peptide
more » ... ain disordered. This disordered binding mechanism involves enthalpically favourable local π-stacking interactions coupled with entropically advantageous global effects. These results indicate that small molecules can stabilise disordered proteins in their native states through transient non-specific interactions that provide enthalpic gain while simultaneously increasing the conformational entropy of the proteins.
doi:10.1101/2021.11.10.468059 fatcat:zpnkfshnkjhhzbdfzd3hyyutku