As examples, “other” type structures have also been used to refer to loop structures that do not form the strict hydrogen-bond pairings present in different types of tight turns, to unfolded structures present in thermally- or chemically- treated proteins which have lost their tertiary structural interactions, or to intrinsically disordered regions (IDRs) of proteins which do not adopt regular helical or sheet structures. Indeed, computationally, the “other” type of secondary structure is often simply ascribed to the remainder of the protein that is not calculated to be helical, sheet, or in some cases, turn. Empirical analyses of proteins with such features rely on the availability of examples of protein spectra which include non-canonical structures in their reference datasets however currently-available reference datasets used by the CD methods have been derived from proteins that crystallise, and therefore tend to include only limited numbers of examples of natively “unordered” or disordered types of secondary structure (which tend to be missing in crystal structures) and are often referred to as “other”. Such residues usually have been grouped together under nomenclatures such as “other”, “unordered”, “irregular”, “disordered” or “random coil”. These types of analyses, however, can be of limited value if the protein to be analysed includes significant numbers of residues that are not present in canonical types of secondary structures.
In most cases, the analyses employ empirical methods that rely on the availability of suitable and broadly-based reference datasets (RDS) derived from proteins with known crystal structures 8, 9, 10. In humans, for instance, ~80% of “hub” proteins with >10 known binding partners are predicted to contain long disordered regions 4.Ĭircular dichroism (CD) spectroscopy (and the related method of synchrotron radiation circular dichroism (SRCD) spectroscopy 5) are widely-used techniques for quantitatively analysing the helix, sheet and turn contents of proteins 6, 7 in different environments and as components of complexes. This is likely to be a reason why they appear to be involved in a number of regulatory functions, including molecular recognition and signalling 3. Due to their flexible nature, IDPs and proteins with IDRs have the potential to bind to a range of partner molecules, acquiring different conformations according to the templates provided by the binding partners. In addition, some globular proteins also exhibit intrinsically disordered regions (IDRs) comprised of ~30 or more consecutive amino acid residues, which do not adopt regular secondary structures 2. In contrast, intrinsically disordered proteins (IDPs) tend to form dynamic ensembles of highly flexible polypeptide chains that often have very limited amounts of persistent secondary structures 1. Most globular proteins in their native state are primarily comprised of canonical (helical, sheet and turn) secondary structures and exist in well-defined conformations with specific three-dimensional structures. DichroIDP enables secondary structure determinations of IDPs and proteins containing intrinsically disordered regions.
This work describes the creation, validation and testing of a standalone Windows-based application, DichroIDP, and a new reference dataset, IDP175, which is suitable for analyses of proteins containing significant amounts of disordered structure. Circular dichroism (CD) spectroscopy is a widely-used method for characterising protein secondary structures, but analyses of IDPs using CD spectroscopy have suffered because the methods and reference datasets used for the empirical determination of secondary structures do not contain adequate representations of unordered structures.
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They play important roles in a broad range of biological processes, such as molecular recognition and signalling, largely due to their chameleon-like ability to change structure from unordered when free in solution to ordered when bound to partner molecules. Intrinsically disordered proteins (IDPs) are comprised of significant numbers of residues that form neither helix, sheet, nor any other canonical type of secondary structure.
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