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.
Show 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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