Spontaneous Switching among Conformational Ensembles in Intrinsically Disordered Proteins

Abstract

The common conception of intrinsically disordered proteins (IDPs) is that they stochastically sample all possible configurations driven by thermal fluctuations. This is certainly true for many IDPs, which behave as swollen random coils that can be described using polymer models developed for homopolymers. However, the variability in interaction energy between different amino acid sequences provides the possibility that some configurations may be strongly preferred while others are forbidden. In compact globular IDPs, core hydration and packing density can vary between segments of the polypeptide chain leading to complex conformational dynamics. Here, we describe a growing number of proteins that appear intrinsically disordered by biochemical and bioinformatic characterization but switch between restricted regions of conformational space. In some cases, spontaneous switching between conformational ensembles was directly observed, but few methods can identify when an IDP is acting as a restricted chain. Such switching between disparate corners of conformational space could bias ligand binding and regulate the volume of IDPs acting as structural or entropic elements. Thus, mapping the accessible energy landscape and capturing dynamics across a wide range of timescales are essential to recognize when an IDP is acting as such a switch.

Features of molecular recognition of intrinsically disordered proteins via coupled folding and binding

“…Which mechanism dominates during the binding process depends on several factors, including the structure preference and conformational dynamics of the IDPs/IDRs, the association rate, and the concentration as well . It has been established that IDPs/IDRs sample a variety of conformations rapidly . At one extreme, if the conformation ensemble of an IDP/IDR in the unbound state is completely different from that in the bound state, it is expected that the binding process proceeds via the induced fit mechanism.…”

“…[114][115][116][117][118][119][120][121][122][123][124][125] It has been established that IDPs/IDRs sample a variety of conformations rapidly. [126][127][128][129] At one extreme, if the conformation ensemble of an IDP/IDR in the unbound state is completely different from that in the bound state, it is expected that the binding process proceeds via the induced fit mechanism. Except this extreme condition, (partially) bound-like conformations could be sampled by the free IDPs/IDRs.…”

Expansion of Intrinsically Disordered Proteins Increases the Range of Stability of Liquid–Liquid Phase Separation

“…The conformational switching behaviour of IDRs can be regulated by many different external events, such as changes in the physiological conditions as ion influx [ 48 ], or introduction of post-translational modifications such as phosphorylation [ 49 , 50 , 51 ]. Also, spontaneous switching among different conformational ensembles has been reported for the C-terminal tail of the GluN2B subunit of the N-methyl-D-aspartate receptor [ 52 ], where post-translational modifications or fluctuations in the ion concentration and/or pH drive the IDRs to switch between alternate conformational ensembles.…”

Intrinsically Disordered Proteins in Chronic Diseases

“…It is one of the few approaches that are sensitive to transient populations of substrates within molecular ensembles, and therefore, is ideally suited to discern conformational preferences of IDP/IDPR ensembles. The first paper in the section, ‘Spontaneous switching among conformational ensembles in intrinsically disordered proteins’, by Choi et al [39] describes a growing number of proteins that appear intrinsically disordered by biochemical and bioinformatics characterization but switch between restricted regions of conformational space. Such switching between disparate corners of conformational space could bias ligand binding and regulate the volume of IDPs acting as structural or entropic elements.…”

“…Such switching between disparate corners of conformational space could bias ligand binding and regulate the volume of IDPs acting as structural or entropic elements. Therefore, mapping the accessible energy landscape and capturing dynamics across a wide range of timescales are essential for recognition of when an IDP/IDPR is acting as such a switch [39]. In the paper entitled ‘Extreme fuzziness: Direct interactions between two IDPs’, Wang and Wang [40] examined whether two IDPs can interact directly to form a fuzzy complex without disorder-to-order transition.…”