On the Importance of Polar Interactions for Complexes Containing Intrinsically Disordered Proteins

Abstract

There is a growing recognition for the importance of proteins with large intrinsically disordered (ID) segments in cell signaling and regulation. ID segments in these proteins often harbor regions that mediate molecular recognition. Coupled folding and binding of the recognition regions has been proposed to confer high specificity to interactions involving ID segments. However, researchers recently questioned the origin of the interaction specificity of ID proteins because of the overrepresentation of hydrophobic residues in their interaction interfaces. Here, we focused on the role of polar and charged residues in interactions mediated by ID segments. Making use of the extended nature of most ID segments when in complex with globular proteins, we first identified large numbers of complexes between globular proteins and ID segments by using radius-of-gyration-based selection criteria. Consistent with previous studies, we found the interfaces of these complexes to be enriched in hydrophobic residues, and that these residues contribute significantly to the stability of the interaction interface. However, our analyses also show that polar interactions play a larger role in these complexes than in structured protein complexes. Computational alanine scanning and salt-bridge analysis indicate that interfaces in ID complexes are highly complementary with respect to electrostatics, more so than interfaces of globular proteins. Follow-up calculations of the electrostatic contributions to the free energy of binding uncovered significantly stronger Coulombic interactions in complexes harbouring ID segments than in structured protein complexes. However, they are counter-balanced by even higher polar-desolvation penalties. We propose that polar interactions are a key contributing factor to the observed high specificity of ID segment-mediated interactions.

Introducing Protein Intrinsic Disorder

“…234 In a recent study, although enrichment in hydrophobic residues was confirmed, polar interactions were found to play a larger role in these complexes than in structured protein complexes, with interfaces being more complementary with respect to electrostatics than interfaces of globular proteins. 238 3) Interaction energies at the interface. Ordered proteins tend to establish more stabilizing interactions within their polypeptide chains, whereas IDPs derive more stabilization from the interaction with the partner.…”

Advantages of proteins being disordered

“…The reason is the same perturbation caused larger mutation enthalpy (ΔΔ H ) in IDPs . Recently, an analysis of protein‐protein complexes from the Protein Data Bank revealed that polar interface interactions make a larger contribution to the specificity in IDPs, and the follow‐up computational alanine scanning of both hydrophobic and charged residues confirmed that these mutations caused larger ΔΔ H in IDPs . Therefore, IDPs are likely to possess high specificity, although maybe not as high as ordered proteins.…”

Linking structural features of protein complexes and biological function

“…The classical work by Chothia and Janin with three protein complexes defined ‘hydrophobicity’ (nonpolar interactions) as the major stabilizing factor in PPI, which has been affirmed with larger datasets of protein complexes . Conversely, shape complementarity, polar interactions, hydrogen bonding, and salt bridges are believed to primarily contribute to binding specificity and free energy of binding . Furthermore, a number of physicochemical factors known to govern protein–protein association include interface size, planarity, sphericity, complementarity, types of amino acid chemical groups, hydrophobicity, electrostatic interactions, H‐bonds, distribution of binding energy, sequence conservation, and conserved residue clusters .…”