Abstract
Intrinsically disordered proteins and protein regions (IDRs) make up around 30% of the human proteome where they play essential roles in dictating and regulating many core biological processes. While IDRs are often studied as isolated domains, in naturally occurring proteins most IDRs are found adjacent to folded domains, where they exist as either N- or C-terminal tails or as linkers connecting two folded domains. Prior work has shown that charge properties of IDRs can influence their conformational behavior, both in isolation and in the context of folded domains. In contrast, the converse scenario is less well-explored: how do the charge properties of folded domains influence IDR conformational behavior? To answer this question, we combined a large-scale structural bioinformatics analysis with all-atom implicit solvent simulations of both rationally designed and naturally occurring proteins. Our results reveal three key takeaways. Firstly, the relative position and accessibility of charged residues across the surface of a folded domain can dictate IDR conformational behavior, overriding expectations based on net surface charge properties. Secondly, naturally occurring proteins possess multiple charge patches that are physically accessible to local IDRs. Finally, even modest changes in the local electrostatic environment of a folded domain can substantially modulate IDR-folded domain interactions. Taken together, our results suggest that folded domain surfaces can act as local determinants of IDR conformational behavior.