Search bioRxiv⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2022.03.05.483089

Soft disorder modulates the assembly path of protein complexes

Seoane, B.·Carbone, A.
View original source ↗Export metadata ↓

Abstract

The relationship between interactions, flexibility and disorder in proteins has been explored from many angles over the years: folding upon binding, flexibility of the core relative to the periphery, entropy changes, etc. In this work, we provide statistical evidence for the involvement of highly mobile and disordered regions in complex assembly. We ordered the entire set of X-ray crystallographic structures in the Protein Data Bank into hierarchies of progressive interactions involving identical or very similar protein chains, yielding 40205 hierarchies of protein complexes with increasing numbers of partners. We then examine them as proxies for the assembly pathways. Using this database, we show that upon oligomerisation, the new interfaces tend to be observed at residues that were characterised as softly disordered (flexible, amorphous or missing residues) in the complexes preceding them in the hierarchy. We also rule out the possibility that this correlation is just a surface effect by restricting the analysis to residues on the surface of the complexes. Interestingly, we find that the location of soft disordered residues in the sequence changes as the number of partners increases. Our results show that there is a general mechanism for protein assembly that involves soft disorder and modulates the way protein complexes are assembled. This work highlights the difficulty of predicting the structure of large protein complexes from sequence and emphasises the importance of linking predictors of soft disorder to the next generation of predictors of complex structure. Finally, we investigate the relationship between the Alphafold2s confidence metric pLDDT for structure prediction in unbound versus bound structures, and soft disorder. We show a strong correlation between Alphafold2 low confidence residues and the union of all regions of soft disorder observed in the hierarchy. This paves the way for using the pLDDT metric as a proxy for predicting interfaces and assembly paths. AvailabilityAll the data used for these analyses (hierarchies of interactions and soft disorder) are available at the website http://www.lcqb.upmc.fr/softdisorder-assembly/. Author summaryBoth flexibility and intrinsic disorder are used as regulatory mechanisms in proteins. They can alter the spatial positions of important recognition sites, and increased mobility appears to facilitate ligand binding through conformational selection. In this work, we show statistical evidence that soft disorder is directly involved in the process of protein assembly and that migration of soft disorder after binding gives rise to new or altered functions in the protein complex. Given the impressive progress that AlphaFold2 has made in protein structure prediction in recent years, this work highlights the importance of also correctly predicting conformational heterogeneity, mobility and intrinsic disorder in order to access the full functional repertoire and interaction network of a given protein.

Source connections

Explore related subjects

bioinformaticsPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Seoane, B., Carbone, A.. 2022-03-07. Soft disorder modulates the assembly path of protein complexes. https://doi.org/10.1101/2022.03.05.483089

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

spatialMET: an open and scalable framework for spatial metabolomics analysis

Mass spectrometry imaging (MSI) enables spatially resolved metabolomics in intact tissue sections, but analysis remains challenging at scale. Existing MSI workflows often require users to combine multiple software tools, while others rely on proprietary vendor software that limits interoperability and reproducibility. To address these challenges, we developed spatialMET, an open-source framework that provides an end-to-end workflow for MSI analysis. spatialMET provides a unified platform for preprocessing, spatial domain detection, and visualization. Downstream analyses include differential abundance testing, spatial autocorrelation and gradient analysis, dimensionality reduction, and correlation network analysis. Spatial domain detection uses hcdist, a C-based hierarchical clustering implementation that substantially reduces runtime and memory use relative to existing R-based approaches. spatialMET can be run through an interactive R Shiny application or as a standalone command-line workflow for larger datasets or high-performance computing environments. Applied to mouse small cell lung cancer MALDI-MSI data containing 284,673 pixels, spatialMET identified tumor-associated, stromal, and adjacent lung spatial domains that aligned with matched histology. Differential abundance analysis identified 117 m/z features that differed between tumor and stromal regions, while spatial autocorrelation analyses revealed spatially structured abundance patterns. Applying spatialMET to mouse lung adenocarcinoma data from an entire lung lobe containing 338,477 pixels further demonstrated scalability and captured spatial heterogeneity across tumor and surrounding lung tissue. In summary, spatialMET provides a scalable, open-source framework for end-to-end spatial metabolomics analysis, and it is distributed as a Docker container for reproducible deployment. Source code and installation instructions are available at https://github.com/biodatalab/spatialMET.

bioinformatics↗
bioRxiv2026

Probing the transcriptome response to shivering in skeletal muscle using a multilayered bioinformatics approach

Cold acclimation holds therapeutic potential for improving metabolic health. We previously demonstrated that repeated cold-induced shivering enhances insulin sensitivity in humans. However, the molecular pathways that underlie the skeletal muscle shivering response, and how these relate to beneficial physiological effects, remain poorly understood. In this study, we combined complementary bioinformatics approaches to allow in-depth analysis of the transcriptomic response of human skeletal muscle to repeated shivering. We identified a robust transcriptional signature and show a sex-specific component in the shivering skeletal muscle response, which seemed to diminish following cold adaptation. Our findings provide mechanistic insights into cold-induced muscle adaptations, shed light on potential interesting molecular targets for further investigation, and emphasize the importance of including both sexes in future cold acclimation studies.

bioinformatics↗
bioRxiv2026

An Information Geometry approach to model topological trajectories and Gene Expression Radius from UMAP geometry.

Understanding the relationship between gene expression dynamics and cellular identity remains a central challenge in single cell biology. Here, we introduce a novel computational and mathematical framework that integrates information geometry, fuzzy topology, and UMAP analysis to model gene expression landscapes derived from single cell RNA sequencing data. We formalize gene expression data as a fuzzy topological space, where interactions between expression points are governed by probabilistic distributions inspired by manifold learning approaches such as UMAP. Within this framework, we define an information geometric structure through a Fisher metric induced by these distributions, enabling the computation of geodesic trajectories that capture cellular differentiation processes. A key contribution of this work is the derivation of analytical conditions, expressed as expression radius formulas, that characterize local neighborhoods in gene expression space. These conditions allow for the identification of genes associated with stem cell states and predictions in transitional cell types in future work. Application of the proposed framework to single cell datasets reveals biologically meaningful gene sets enriched in key regulatory pathways and transcription factors, demonstrating the capacity of our approach to uncover latent structure in complex gene expression data. Our results suggest that integrating differential geometry with statistical learning theory offers a powerful paradigm for modeling genotype and phenotype relationships and cellular state transitions, with potential implications for precision medicine and systems biology.

bioinformatics↗