Multiscale ensemble modeling of intrinsically disordered proteins: p53 N-terminal domain

Intrinsically disordered proteins (IDPs) are ubiquitous and play key roles in transcriptional regulations and other cellular processes. To characterize diverse structural ensembles of IDPs, combinations of NMR and computational modeling showed some promise, but they need further improvements. Here, for accurate and efficient modeling of IDPs, we propose a systematic multiscale computational method. We first perform all-atom replica-exchange molecular dynamics (MD) simulations of a few fragments selected from a target IDP. These results together with generic knowledge-based local potentials are fed into the iterative Boltzmann inversion method to obtain an accurate coarse-grained potential. Then coarse-grained MD simulations provide the IDP ensemble. We tested the new method for the disordered N-terminal domain of p53 showing that the method reproduced the residual dipolar coupling and x-ray scattering profile very accurately. Further local structure analyses revealed that, guided by all-atom MD ensemble of fragments, the p53 N-terminal domain ensemble was biased to kinked structures in the AD1 region and biased to extended conformers in a proline-rich region and these biases contributed to improvement of the reproduction of the experiments.