Exploring the Functional Landscape of the p53 Regulatory Domain: The Stabilizing Role of Post-Translational Modifications

Abstract

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.

Deeper Insight of the Conformational Ensemble of Intrinsically Disordered Proteins

“…Deeptime was used to implement time-lagged independent component analysis, tICA. This approach enabled us to construct free energy and solvent-accessible surface area, SASA, landscapes with aid from the Pyemma and MDtraj packages, respectively, as described in previous works. , χ 2 was calculated to compare experiment data to simulation data using eq where N is the number of data points, E i is the experimental data point, and S i is the simulated data point χ normal2 = prefix∑ i = 1 N false( E i − S i false) 2 S i …”