Abstract
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 that can be a key determinant of their activity. With no extensive network of non-covalent bonds and a high propensity for exposed surface areas, the various features of an IDR’s ensemble – including 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. By tuning the interactions of specific protein moieties with the solution in a systematic manner we can both enhance and reduce local residual structure. This approach allows the ‘design’ of distinct residual structures in IDRs, offering an alternative approach to mutational studies for exploring sequence-to-ensemble relationships. Our results raise the possibility of solution-based regulation of protein functions both outside and within the dynamic solution environment of cells.
