Impact of Hydrophobic Patterning on Conformational Ensemble of Disordered Proteins

Abstract

Understanding the conformational ensemble of an intrinsically disordered protein (IDP) is of great interest due to its relevance to important intracellular functions and diseases. We have recently shown that the polymer scaling exponent characterizing the dependence of protein size on chain length is a crucial factor as it strongly correlates with liquid-liquid phase behavior of an IDP. Previously, sequence properties from charged amino acids, including both fraction of positive/negative charges and charge patterning have been acknowledged to affect the size of an IDP. However, IDP sequences are composed of a significant amount of uncharged amino acids and how these uncharged amino acids impact the size of an IDP is not well understood. Here, we first investigate if average hydrophobicity can be used to obtain quantitative insights into the polymer scaling properties of IDP sequences. Based on the coarse-grained simulation data for a large number of uncharged IDPs, we find that incorporating the information about the patterning of residues is necessary to model the size of an IDP faithfully. The newly developed sequence hydrophobicity decoration (SHD) parameter, together with the previously known sequence charge decoration (SCD) parameter, can be used to predict the size of an IDP. Our results are, therefore, a significant step forward to elucidate the fundamental principles governing the sequence-structure relationships of disordered proteins.