This study focuses on the intrinsically disordered regulatory domain of p53 and the impact of post-translational modifications. Through fully atomistic explicit water molecular dynamics simulations, we show the wealth of information and detailed understanding that can be obtained by varying the number of phosphorylated amino acids and implementing a restriction in the conformational entropy of the N-termini of that intrinsically disordered region. The take-home message for the reader is to achieve a detailed understanding of the impact of phosphorylation with respect to (1) the conformational dynamics and flexibility, (2) structural effects, (3) protein interactivity, and (4) energy landscapes and conformational ensembles. Although our model system is the regulatory domain p53 of the tumor suppressor protein p53, this study contributes to understanding the general effects of intrinsically disordered phosphorylated proteins and the impact of phosphorylated groups, more specifically, how minor changes in the primary sequence can affect the properties mentioned above.

Division of Computational Chemistry Department of Chemistry Lund University P O Box 124 221 00 Lund Sweden

Faculty of Pharmacy in Hradec Králové Charles University Akademika Heyrovského 1203 8 500 05 Hradec Králové Czech Republic

MAX 4 Laboratory Fotongatan 2 224 84 Lund Sweden

NanoLund Lund University Box 118 221 00 Lund Sweden

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Deeper Insight of the Conformational Ensemble of Intrinsically Disordered Proteins