Investigating the Conformational Ensembles of Intrinsically Disordered Proteins with a Simple Physics-Based Model

Abstract

The interactions of intrinsically disordered proteins (IDPs) play an important role in biological processes but present a number of fundamental challenges for computational modeling. While single chain conformational dynamics can be described by coarse-grained models with near-atomic resolution and specialized implicit solvent interactions, much simpler models are often adopted for investigating interactions between multiple IDPs. In fact, simple polymer models have regained popularity for interpreting the experimental characterization of IDPs. Homopolymer theory provides a strong foundation for understanding generic features of phenomena ranging from single chain conformational dynamics to the properties of entangled polymer melts, but is difficult to extend to the copolymer context. This challenge is magnified for proteins due to the variety of competing interactions and large deviations in side-chain properties. In this work, we apply a simple physics-based coarse-grained model for describing largely disordered conformational ensembles of peptides, based on the premise that sampling sterically-forbidden conformations can compromise the faithful description of both static and dynamical properties. The Hamiltonian of the employed model can be easily adjusted to investigate the impact of distinct interactions and sequence specificity on the randomness of the resulting conformational ensemble. We utilize this feature to explore various possible unbound ensembles for an IDP that undergoes coupled folding and binding. In particular, starting with a bead-spring-like model and then adding more detailed interactions one by one, we construct a hierarchical set of models and perform a detailed comparison of their properties. Our analysis clarifies the role of generic attractions, electrostatics and side-chain sterics, while providing a foundation for developing efficient models for IDPs that retain an accurate description of the hierarchy of conformational dynamics, which is nontrivially influenced by interactions with surrounding proteins.