Theoretical perspectives on nonnative interactions and intrinsic disorder in protein folding and binding.

The diverse biological functions of intrinsically disordered proteins (IDPs) have markedly raised our appreciation of protein conformational versatility, whereas the existence of energetically favorable yet functional detrimental nonnative interactions underscores the physical limitations of evolutionary optimization. Here we survey recent advances in using biophysical modeling to gain insight into experimentally observed nonnative behaviors and IDP properties. Simulations of IDP interactions to date focus mostly on coupled folding-binding, which follows essentially the same organizing principle as the local-nonlocal coupling mechanism in cooperative folding of monomeric globular proteins. By contrast, more innovative theories of electrostatic and aromatic interactions are needed for the conceptually novel but less-explored 'fuzzy' complexes in which the functionally bound IDPs remain largely disordered.