CIDER: Resources to Analyze Sequence-Ensemble Relationships of Intrinsically Disordered Proteins

Abstract

Intrinsically disordered proteins and regions (IDPs) represent a large class of proteins that are defined by conformational heterogeneity and lack of persistent tertiary/secondary structure. IDPs play important roles in a range of biological functions, and their dysregulation is central to numerous diseases, including neurodegeneration and cancer. The conformational ensembles of IDPs are encoded by their amino acid sequences. Here, we present two computational tools that are designed to enable rapid and high-throughput analyses of a wide range of physicochemical properties encoded by IDP sequences. The first, CIDER, is a user-friendly webserver that enables rapid analysis of IDP sequences. The second, localCIDER, is a high-performance software package that enables a wide range of analyses relevant to IDP sequences. In addition to introducing the two packages, we demonstrate the utility of these resources using examples where sequence analysis offers biophysical insights.

Figure 1

(a) Diagram of states annotated with representative conformations for specific IDPs that correspond to each of the five regions. (b) Schematic depiction of the implication of changing κ values. Here, red and blue circles represent negatively charged residues and positively charged residues, respectively.

Figure 2

Overview of a subset of the output generated by CIDER. (a) Overview of the parameters that are calculated. When multiple sequences are analyzed, each column is sortable. (b–d) A sliding-window approach is used to show the linear hydrophobicity, NCPR, and FCR, respectively. (e) The physicochemically colored sequence. Here, black denotes hydrophobic residues, green denotes polar residues, and blue and red denote positive and negatively charged residues, respectively. (f) A sequence-annotated diagram of states.

Figure 3

Three examples of linear sequence analysis performed by localCIDER. (a) Charge patterning in the protein DDX4, identifying the local region with a high net positive or negative charge and showing the full-sequence and C-terminal κ values. (b) Illustration of the local sequence composition and complexity of the protein FUS. RNA recognition motifs (RRM) and Zinc-finger domains (Zn-Fin) are annotated based on published structural information. (c) Charge distribution in the 4R-441 isoform, with various domains and regions annotated.