How Do Interactions in Cis with Ordered Domains Influence Sequence-Ensemble Relationships of Intrinsically Disordered Regions?

Abstract

The conformational properties of intrinsically disordered proteins (IDPs) are governed by their amino acid sequences. An overwhelming majority of disordered regions are often found in cis with ordered domains as terminal tails or inter-domain linkers. The motivating question is if the rules governing sequence-ensemble relationships that have been inferred for IDPs as autonomous units apply for describing the conformational properties of disordered regions in cis to ordered domains. Using atomistic simulations and fluorescence studies we characterize the conformational properties of several archetypes of intrinsically disordered sequences in the presence and absence of cis-acting ordered domains. In particular, we quantify the effects of sequence composition, chain length, and sequence patterning of disordered sequences on the inter-domain coupling. The balance between intra-domain and inter-domain interactions can modulate intrinsic conformational propensities of the disordered regions. The circumstances giving rise to convergence toward generic random-coil behavior for disordered regions in cis to ordered domains will be highlighted.