Globular and disordered-the non-identical twins in protein-protein interactions

Abstract

In biology proteins from different structural classes interact across and within classes in ways that are optimized to achieve balanced functional outputs. The interactions between intrinsically disordered proteins (IDPs) and other proteins rely on changes in flexibility and this is seen as a strong determinant for their function. This has fostered the notion that IDP's bind with low affinity but high specificity. Here we have analyzed available detailed thermodynamic data for protein-protein interactions to put to the test if the thermodynamic profiles of IDP interactions differ from those of other protein-protein interactions. We find that ordered proteins and the disordered ones act as non-identical twins operating by similar principles but where the disordered proteins complexes are on average less stable by 2.5 kcal mol(-1).

Keywords: IDP; ITC; enthalpy; entropy; intrinsically disordered; stability.

Figure 1

Amino acid composition of protein-protein interfaces extracted from 87 high-resolution structures of protein-protein complexes. (A) Fractional overrepresentation of each amino acid residue type and of the four amino acid residue classes (FWY, CILMV, AGPST, and DEHKNQR) in ORD-IDP complexes relative to ORD-ORD complexes. log₂ of the ratios are plotted with positive values indicating overrepresentation in ORD-IDP complexes. (B) Correlation plots of the fractions of the four amino acid residue classes (FWY, CILMV, AGPST, and DEHKNQR) in protein-protein interfaces. Each point represents a protein-protein complex and is colored either red (ORD-ORD) or blue (ORD-IDP).

Figure 2

Thermodynamics of 196 protein-protein complexes. (A) Histogram of the binding free energy, ΔG°, for complexes between two ordered proteins (red) and one ordered and one disordered protein (blue). Both distributions were fit to a Gaussian distribution (solid lines). (B) Plot of ΔH° versus TΔS° for the same protein–protein complexes with the same color code as in (A). The solid lines represent the best linear fits to the data.