Controlling Structural Bias in Intrinsically Disordered Proteins Using Solution Space Scanning

Intrinsically disordered proteins or regions (IDRs) differ from their well-folded counterparts by lacking a stable tertiary state. Instead, IDRs exist in an ensemble of conformations and often possess localized, loosely held residual structure, which can be a key determinant of their activity. With no extensive network of noncovalent bonds and a high propensity for exposed surface areas, various features of an IDR's ensemble - including the local residual structure and global conformational biases - are an emergent property of both the amino acid sequence and the solution environment. Here, we attempt to understand how shifting solution conditions can alter an IDR's ensemble. We present an efficient computational method to alter solution-protein interactions we term Solution Space (SolSpace) Scanning. SolSpace scanning uses all-atom Monte Carlo simulations to construct ensembles under a wide range of distinct solution conditions. We find that by tuning the interactions of specific protein moieties with the solution in a systematic manner, we can not only alter IDR global dimensions but also completely change the local residual structure in a sequence. SolSpace scanning therefore offers an alternative approach to mutational studies for exploring sequence-to-ensemble relationships in IDRs. Our results raise the possibility of solution-based regulation of IDR functions both outside and within the dynamic environment of cells.