Direct prediction of intermolecular interactions driven by disordered regions

Abstract

Intrinsically disordered regions (IDRs) are critical for a wide variety of cellular functions, many of which involve interactions with partner proteins. Molecular recognition is typically considered through the lens of sequence-specific binding events. However, 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 the amino acid order, instead driven by complementary chemical interactions leading to disordered bound-state complexes. Despite this emerging paradigm, we lack tools to describe, quantify, predict, and interpret these types of structurally heterogeneous interactions from the underlying amino acid sequences. Here, we repurpose the chemical physics developed originally for molecular simulations to develop an approach for predicting intermolecular interactions between IDRs and partner proteins. Our approach enables the direct prediction of phase diagrams, the identification of chemically-specific interaction hotspots on IDRs, and a route to develop and test mechanistic hypotheses regarding IDR function in the context of molecular recognition. We use our approach to examine a range of systems and questions to highlight its versatility and applicability.

Protein surface chemistry encodes an adaptive resistance to desiccation

“…To understand the consequences of the observed trends in surface chemistry, we calculated predicted mean-field interactions between each domain's surface residues and a set of thirty-six previously identified dipeptide repeats (see Methods ) ( Fig. 4G ) ( 30 ) . These test peptides encapsulate a chemically diverse set of chemistries and allow us to test how different globular domain surfaces may interact with various types of putative partners.…”

“…We previously performed systematic clustering of all possible peptides to identify a minimal set of 36 distinct peptides that are chemically orthogonal to one another (see Fig. S11 in Ginell et al ( 30 ) ). For each individual globular domain, we calculated the average mean-field attractive interaction between the surface of the domain and each of these 36 peptides, enabling us to determine domains where more or less attractive for different types of chemistry.…”