Analysis of Protein Disorder Predictions in the Light of a Protein Structural Alphabet

Abstract

Intrinsically-disordered protein (IDP) characterization was an amazing change of paradigm in our classical sequence-structure-function theory. Moreover, IDPs are over-represented in major disease pathways and are now often targeted using small molecules for therapeutic purposes. This has had created a complex continuum from order-that encompasses rigid and flexible regions-to disorder regions; the latter being not accessible through classical crystallographic methodologies. In X-ray structures, the notion of order is dictated by access to resolved atom positions, providing rigidity and flexibility information with low and high experimental B-factors, while disorder is associated with the missing (non-resolved) residues. Nonetheless, some rigid regions can be found in disorder regions. Using ensembles of IDPs, their local conformations were analyzed in the light of a structural alphabet. An entropy index derived from this structural alphabet allowed us to propose a continuum of states from rigidity to flexibility and finally disorder. In this study, the analysis was extended to comparing these results to disorder predictions, underlying a limited correlation, and so opening new ideas to characterize and predict disorder.

New insights into disordered proteins and regions according to the FOD-M model

“…This is the case when the available structure of the complex gives the form obtained by the protein when it interacts with another component of the complex. The form of the interface, which in the free protein takes the form of IDP, already represents a static form in the complex [ 10 – 12 ]. The participation of IDPs in the context of a specific biological process—often critical for functioning—is important [ 13 , 14 ].…”

Analysis of Integrin αIIb Subunit Dynamics Reveals Long-Range Effects of Missense Mutations on Calf Domains

“…The height of letters indicates the relative frequency of PB at that position, i.e., one big letter means only one type of PB, and small and numerous letters show higher diversity. N eq values have been scaled in regard to flexible and disordered regions [ 30 , 31 ]. N eq value higher than 8 is considered as disordered position, whereas values less than 8 but greater than 6 are considered highly flexible, and values around 4 show inherent flexibility.…”

“…Figure 6 c,g show that these loops are not completely disordered, but they have specific regions. In regard to a specific rigid region encompassed between highly disordered regions [ 5 , 31 ], they were analyzed in depth [ 32 ]. The first completed loop begins with a slightly deformable region (before position 767, N eq is around 2), before going to the restricted disorder position 768, and the rest of the loop is between flexible and highly flexible.…”

“…They were completed using restraints guided by biophysical expertise and then subjected to MD simulations. The dynamics of the completed loops revealed high intrinsic flexibility, but not any disorder (as defined by N eq measure [ 30 , 31 , 42 ]). It is interesting to note that some segments are more rigid than others, which underwent large amplitude of conformational changes.…”

Structural and Dynamic Differences between Calreticulin Mutants Associated with Essential Thrombocythemia

“…Additionally, we wanted to verify our hypothesis that class E is only a polymorphism of CALRwt and is not associated with ET. To achieve this, we used molecular dynamics simulations to reproduce the theoretical dynamics of each CALRm class in monomeric and dimeric forms, and we analyzed them with Protein Blocks [ 71 , 84 ].…”