Search

Additional file 1 Supplementary Figures S1-S5 with each legend. Fig S1. Meta-Hi-C network benchmarking in mouse. Fig S2. Meta-Hi-C network benchmarking in human. Fig S3. TAD coexpression vs contact coexpression. Fig S4. TAD and boundary conservation across experiments. Fig. S5. Contact coexpression conservation at various coexpression thresholds.

Additional file 3 Review history.

A hierarchical sequence-based framework for analysis and conceptualization of intrinsically disordered proteins (IDPs) is presented. This framework was further used to develop a novel test for enrichment of higher-order (tertiary) structure in a disordered protein using Molecular Dynamics (MD) simulations and Monte Carlo simulations. Finally, we show that the developed framework can also serve as a useful tool in predicting the consequence of an amino acid substitution on the IDPs function using a bioinformatics approach. In structured proteins, contacts between residues distant along the sequence are reflected in the tertiary structure, but developing a framework for describing the analogous property in IDPs has not been straightforward. The distribution of hydrophobic residues within the sequence was used to identify 4-15 residues `blobs' representing local globular regions or linkers. We use this framework within a novel test for enrichment of higher-order (tertiary) structure in disordered proteins; the size and shape of each blob is extracted from MD simulation of the real protein (RP) and used to parameterize a self-avoiding heterogeneous polymer (SAHP). In our study on the 91-residue disordered prodomain of brain derived neurotrophic factor (BDNF), we find that the long 15 residue linker itself creates a segmentation in contact pair map for both SAHP and RP. We find that in RP only the contact between the segmented region is enriched relative to SAHP. We further quantified the enrichment observed for several other hydrophobic substitutions within the disordered prodomain, including the disease-causing Val66Met substitution. We find that in RPs the enrichment observed in the contact between the segmented region is sensitive to amino acid substitution as well. Only the disease-associated Met66 substitution enriches these contacts significantly, due to a preferred Met-Met interaction. Furthermore, we find several properties of the blobs identified with the sequence-based framework which are enriched in disease-associated SNPs relative to non disease-associated SNPs. This allowed us to present the first systematic, bottom-up, attempt to both identify and annotate subdomains within disordered proteins that are enriched for functional effects.

Motivation: Clusters of hydrophobic residues are known to promote structured protein stability and drive protein aggregation. Recent work has shown that identifying contiguous hydrophobic residue clusters (termed "blobs") has proven useful in both intrinsically disordered protein (IDP) simulation and human genome studies. However, a graphical interface was unavailable., Results: Here, we present the blobulator: an interactive and intuitive web interface to detect intrinsic modularity in any protein sequence based on hydrophobicity. We demonstrate three use cases of the blobulator and show how identifying blobs with biologically relevant parameters provides useful information about a globular protein, two orthologous membrane proteins, and an IDP. Other potential applications are discussed, including: predicting protein segments with critical roles in tertiary interactions, providing a definition of local order and disorder with clear edges, and aiding in predicting protein features from sequence., Availability: The blobulator GUI can be found at www.blobulator.branniganlab.org, and the source code with pip installable command line tool can be found on GitHub at www.GitHub.com/BranniganLab/blobulator.