Sequence-based prediction of intermolecular interactions driven by disordered regions.

Abstract

Intrinsically disordered regions (IDRs) in proteins play essential roles in cellular function. A growing body of work has shown that IDRs often interact with partners in a manner that does not depend on the precise order of amino acids but is instead driven by complementary chemical interactions, leading to disordered bound-state complexes. However, these chemically specific dynamic interactions are difficult to predict. In this study, we repurposed the chemical physics developed originally for molecular simulations to predict this chemical specificity between IDRs and partner proteins using protein sequence as the only input. Our approach-FINCHES-enables the direct prediction of phase diagrams, the identification of chemically specific interaction hotspots on IDRs, the decomposition of chemically distinct domains in IDRs, and a route to develop and test mechanistic hypotheses regarding IDR function in molecular recognition.