Sequence and Chemical Environment Determine the Global Dimension of Intrinsically Disordered Protein Ensembles

Abstract

Intrinsically disordered proteins (IDPs) play essential roles in the cell, but do not have a stable native structure. Lacking intramolecular bonds, IDPs exist in a rapidly changing conformational ensemble. These ensembles have a high degree of surface area exposure, making them sensitive to the physical-chemical composition of the cellular environment. The sensitivity of IDPs to their environment can lead to a solution-induced change in both global ensemble dimensions (such as radius of gyration) and local residual structure between residues, which may alter IDP function. To reveal the link between IDP sequence and the sensitivity of its ensemble to physical-chemical changes in its environment we use implicit-solvent Monte Carlo simulations of IDP ensembles in a range of solution conditions using a method we call Solution Space Scanning. We use Solution Space Scanning to compile a dataset containing over 100 naturally occurring IDPs in different solution conditions. Our dataset reveals a staggering range of IDP sensitivities, which shows a weak correlation with sequence length and chain-average molecular features such as hydrophobicity or net charge. Instead, we find a strong correlation between IDPs solution sensitivity and the global dimension of the chain in aqueous buffer. We corroborate our findings with high-throughput experiments and a polymer physics model to establish how sensitivity to solution conditions emerges in intrinsically disordered proteins.