Hierarchically ordered multi-timescale structural dynamics of the intrinsically disordered p53 transactivation domain

Szöllösi, D.; Pratihar, S.; Mukhopadhyay, D.; Rout, A. K.; Reddy, G. J.; Ebersberger, N.; Becker, S.; Nagy, G.; Rauscher, S.; Lee, D.; Klement, R.; Griesinger, C.; Grubmuller, H.

doi:10.1101/2025.08.01.668138

bioRxiv · 10.1101/2025.08.01.668138

Hierarchically ordered multi-timescale structural dynamics of the intrinsically disordered p53 transactivation domain

Szöllösi, D.·Pratihar, S.·Mukhopadhyay, D.·Rout, A. K.·Reddy, G. J.·Ebersberger, N.·Becker, S.·Nagy, G.·Rauscher, S.·Lee, D.·Klement, R.·Griesinger, C.·Grubmuller, H.

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Abstract

Intrinsically disordered proteins (IDPs) exhibit pronounced structural dynamics, which is crucial for their functional versatility. Yet their dynamics slower than nanoseconds remain largely elusive. We combined high-power relaxation dispersion nuclear magnetic resonance spectroscopy with molecular dynamics simulations to characterize these kinetics and the underlying structural interconversions of a prototypical IDP, the N-terminal transactivation domain of the tumor suppressor p53 (p53-TAD). We find a complex hierarchy of structural dynamics on timescales covering over seven orders of magnitude, ranging from fast nanoseconds backbone re-orientations, 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 of p53-TAD, and likely those of other IDPs, parallel the timescale hierarchy of the conformational dynamics of folded proteins. One-Sentence summaryA hierarchical energy landscape governs kinetics and structural dynamics of the disordered p53 transactivation domain.

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Szöllösi, D., Pratihar, S., Mukhopadhyay, D., Rout, A. K., Reddy, G. J., Ebersberger, N., Becker, S., Nagy, G., Rauscher, S., Lee, D., Klement, R., Griesinger, C., Grubmuller, H.. 2025-08-02. Hierarchically ordered multi-timescale structural dynamics of the intrinsically disordered p53 transactivation domain. https://doi.org/10.1101/2025.08.01.668138

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