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bioRxiv · 10.1101/2021.11.10.468059

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

Löhr, T.·Kohlhoff, K.·Heller, G. T.·Camilloni, C.·Vendruscolo, M.
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Abstract

The 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 A{beta}42 peptide, an intrinsically disordered protein fragment associated with Alzheimers disease. We show that this stabilisation takes place by a dynamic binding mechanism, in which both the small molecule and the A{beta}42 peptide remain disordered. This disordered binding mechanism involves enthalpically favourable local {pi}-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.

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Löhr, T., Kohlhoff, K., Heller, G. T., Camilloni, C., Vendruscolo, M.. 2021-11-11. A small molecule stabilises the disordered native state of the Alzheimer's Aβ peptide. https://doi.org/10.1101/2021.11.10.468059

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