Improving the Performance of Simulations of the Intrinsically Disordered N-Terminal Domain from P53

Abstract

Signal transduction in intrinsically disordered proteins (IDPs) is frequently understood in the context of binding-induced folding, but accurate simulations of IDP structures remain computationally challenging. Protein-solvent interactions, electrostatics, and prolyl isomerization all contribute to the complexity of the behavior of IDPs in solution. Previous studies have indicated a relationship between local alterations in Polyproline-II (PPII) propensities and hydrodynamic radius (RH) which serves as an indicator of global structural changes. Unfortunately, extension of these studies to long polypeptide sequences is computationally prohibitive. We are interested in the behavior of the intrinsically disordered N-terminal domain (NTD) of the p53 protein, a 93-residue region involved in multiple protein binding and cell cycle control. In previous work, accurate simulation of hydrodynamic properties has been limited to simple sequences of 50 residues or less, excluding the possibility of modeling the full length NTD. This study builds upon established computational methods to create a more efficient Monte-Carlo simulation of the NTD that retains the chemically-realistic solvation energy calculations employed previously. Our modified simulation is shown to reproduce faithfully the hydrodynamic properties of the NTD, while at the same time running significantly faster for polypeptides larger than 80 amino acids.