Unlike proteins with defined three-dimensional structure, IDPs have been generally designed by nature to natively avoid minimal frustration. For instance, IDPs sequences are enriched in disorder-promoting
ONX-0914 (Pro, Glu, Lys, Ser and Gln) and depleted in order-promoting amino acids (Trp, Tyr, Phe, Cys, Ile, Asn and Leu) [39]. Yet, IDPs may undergo disorder-to-order transitions by binding. If frustration has been natively encoded in IDPs, how exactly is it manifested in nature? Given their global frustrated nature, IDPs can be found in a broad range of conformational states as even small perturbations in the cell can produce significant shifts in their conformational populations. Despite the presence of dissimilar conformational states, one or more short regions within IDPs may be significantly less frustrated compared to the global sequence. Consequently, ‘preformed’ MoRFs/MoREs may emerge from lower frustration imprinted in these small regions. Interestingly,
secondary structure analysis revealed that 27% of the residues in the MoRF/MoRE dataset had α-helical conformation, 12% were β-strands residues, indicating that some structural order has been imprinted in these regions [30]. More importantly, such reduced local frustration is not necessarily manifested as the formation of regions with well defined structure; such phenomenon is supported by the fact that approximately 48% of the MoRF/MoRE dataset were residues of irregular structure [30]. In this sense, the local conformational states arising from the folding funnel are significantly more restricted (i.e. only a reduced number of dissimilar conformational states are sampled in the unbound state) compared to the globally frustrated IDPs. MoRFs/MoREs may display this particular dynamic nature in order to conserve the plasticity required for their anchoring function.
