Hierarchical multi-timescale structural dynamics of the disordered N-terminal of p53

Most natively folded proteins exhibit a unique spatial structure, which undergoes functional motions ranging from picoseconds to seconds, governed by a hierarchically ordered, funnel-shaped free energy landscape. Intrinsically disordered proteins (IDPs) lack such a stable native structure, but undergo fast interconversions between many different structures. Accordingly, the underlying free energy landscape is assumed to be rather shallow and unstructured. However, although IDPs represent nearly one-third of the human proteome, their structural dynamics on timescales slower than nanoseconds remain largely elusive. Here we reveal the structural dynamics of the prototypical IDP p53-TAD, also known as the "guardian of the genome", by combining high-power relaxation dispersion nuclear magnetic resonance spectroscopy with large-scale molecular dynamics simulations. We found a complex hierarchy of structural dynamics on timescales covering over seven orders of magnitude, ranging from fast nanoseconds backbone reorientations, via sub-microsecond helix-formation dynamics involving many structural sub-states and transition times, to transient tertiary structure formation slower than 25 microseconds. These rich structural dynamics are unexpectedly similar to the timescale hierarchy of natively folded proteins, which may be key to the ability of p53-TAD - and possibly of other IDPs - to bind many different partners by folding into different structures.