title: Resolving the ambiguity: Making sense of intrinsic disorder when PDB structures disagree.
abstract: Missing regions in X-ray crystal structures in the Protein Data Bank (PDB) have played a foundational role in the study of intrinsically disordered protein regions (IDPRs), especially in the development of in silico predictors of intrinsic disorder. However, a missing region is only a weak indication of intrinsic disorder, and this uncertainty is compounded by the presence of ambiguous regions, where more than one structure of the same protein sequence "disagrees" in terms of the presence or absence of missing residues. The question is this: are these ambiguous regions intrinsically disordered, or are they the result of static disorder that arises from experimental conditions, ensembles of structures, or domain wobbling? A novel way of looking at ambiguous regions in terms of the pattern between multiple PDB structures has been demonstrated. It was found that the propensity for intrinsic disorder increases as the level of ambiguity decreases. However, it is also shown that ambiguity is more likely to occur as the protein region is placed within different environmental conditions, and even the most ambiguous regions as a set display compositional bias that suggests flexibility. The results suggested that ambiguity is a natural result for many IDPRs crystallized under different conditions and that static disorder and wobbling domains are relatively rare. Instead, it is more likely that ambiguity arises because many of these regions were conditionally or partially disordered.
authors.affiliation: Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida, 33612.
authors.forename: Shelly
authors.initials: S
authors.lastname: DeForte
authors.affiliation: Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida, 33612.|USF Health Byrd Alzheimer's Research Institute, Morsani College of Medicine, University of South Florida, Tampa, Florida, 33612.|Department of Biological Science, Faculty of Science, King Abdulaziz University, PO Box 80203, Jeddah, Jeddah 21589, Saudi Arabia.|Institute for Biological Instrumentation, Russian Academy of Sciences, Pushchino, Moscow Region, 142290, Russian Federation.|Laboratory of Structural Dynamics, Stability and Folding of Proteins, Institute of Cytology, Russian Academy of Sciences, St. Petersburg, Russian Federation.
authors.forename: Vladimir N
authors.initials: VN
authors.lastname: Uversky
mesh_terms: D000595:Amino Acid Sequence; D018360:Crystallography, X-Ray; D030562:Databases, Protein; D064267:Intrinsically Disordered Proteins / Q000737:chemistry*; D011487:Protein Conformation; D017433:Protein Structure, Secondary
chemical_list: D064267:Intrinsically Disordered Proteins
keywords: PDB; X-ray crystallography; disorder prediction; intrinsically disordered protein; intrinsically disordered protein region; missing residues; protein data bank