Describing sequence–ensemble relationships for intrinsically disordered proteins

Emil Fischer proposed that enzyme specificity could be explained by shape complementarity [1, 2]. He used the metaphor of a lock and key to illustrate how the three-dimensional arrangements of atoms comprising an enzyme and its substrate could enable them to fit together and prevent non-specific catalysis. Interpreted literally, this metaphor suggests that proteins possess rigid structures that determine their functions. Fischer, however, felt that popular interpretations of his lock-and-key metaphor exceeded its scope and experimental justification [3]. Indeed, protein rigidity has proven to be unsatisfactory at explaining noncompetitive inhibition and cannot account for enzymes where binding of one reactive group increases the exposure of another [4]. The concepts of allosteric linkage [5] and induced fit require the invocation of protein conformational changes in response to the binding of an interaction partner [6]. The structure-function paradigm, nuanced to accommodate proteins that switch between discrete conformations with different shape complementarities for execution of specific functions provides visual clarity and mathematical simplicity. Going beyond structure-function relationships Advancements on scientific and technological fronts have demonstrated unequivocally that proteins can exhibit significant conformational heterogeneity. Intrinsically disordered proteins (IDPs) are at the extreme end of the heterogeneity spectrum [7-9]. They adopt ensembles of conformations in aqueous solutions for which no single structure or self-similar collection of structures provides an adequate description. By all accounts the conformational heterogeneity exhibited by IDPs is relevant for biological function [8-14]. The phrase intrinsically disordered proteins is used to imply that the amino acid sequences for this class of proteins encode a preference for heterogeneous ensembles of conformations as the thermodynamic ground state under standard physiological conditions (aqueous solutions, 150 mM monovalent salt, low concentrations of divalent ions, pH 7.0, and temperature in the 25°C – 37°C range) [9, 15]. For many IDPs, folding can be coupled to binding and they can adopt ordered structures in specific bound complexes [16-20]. The intrinsic heterogeneity in their unbound forms is reflected in their ability to adopt different folds in the context of different complexes [10]. Transcription factors represent striking examples of molecules that undergo disorder-to-order transitions in complex with their cognate DNA partners [21-24]. Highly stable complexes with DNA can make transcription factor dissociation become “unreasonably slow” when compared to the turnover time of downstream regulatory processes. Disorder in the unbound forms is proposed to be important for lowering the overall affinity, which in turn increases the off-rates of protein-DNA complexes [25]. There are a growing number of reports of “fuzzy complexes” whereby conformational heterogeneity prevails in binary and multimolecular complexes [26-28]. IDPs can also self-assemble to form ordered, supramolecular assemblies, although the degree of order within these assemblies is variable and the intermediates that seem to be obligatory for self-assembly are characterized by significant conformational heterogeneity that can be modulated to alter the mechanisms of self-assembly and the stabilities of supramolecular structures [29-38].