ProteinCT: An implementation of the protein circuit topology framework

Moes, Duane; Banijamali, Elnaz; Sheikhhassani, Vahid; Scalvini, Barbara; Woodard, Jaie; Mashaghi, Alireza

doi:10.1016/j.mex.2022.101861

Cited by 5 publications

(4 citation statements)

References 25 publications

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“…Circuit Topology Analysis: The topology matrix was obtained by custom code, published previously by Moes et al [58] Cutoffs used for contact identification were: distance cutoff = 4.5 Å, number of atom-atom contacts = 5, neighbor exclusion = 4. The contacts were numbered from N to C terminus (residue-residue).…”

Section: Methodsmentioning

confidence: 99%

“…Considering the heterogeneity of processes and interactions taking place between MBP and the cytosolic environment, we also advance a new way to analyze force spectroscopy data, based on the theoretical framework of circuit topology (CT). [19][20][21][22] CT formalizes the arrangement of contacts and loops in a folded chain and thus, disruption and formation of loops as probed in the tweezers assay can be directly modeled by this approach. We can therefore represent such loops and associated contour lengths in the formalism of CT, providing a way to visualize the complete ensemble of unfolding pathways and reconstructing from it the topological fingerprint of the substrate.…”

Section: Introductionmentioning

confidence: 99%

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Cytosolic Interactome Protects Against Protein Unfolding in a Single Molecule Experiment

et al. 2023

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Single molecule techniques are particularly well suited for investigating the processes of protein folding and chaperone assistance. However, current assays provide only a limited perspective on the various ways in which the cellular environment can influence the folding pathway of a protein. In this study, a single molecule mechanical interrogation assay is developed and used to monitor protein unfolding and refolding within a cytosolic solution. This allows to test the cumulative topological effect of the cytoplasmic interactome on the folding process. The results reveal a stabilization against forced unfolding for partial folds, which are attributed to the protective effect of the cytoplasmic environment against unfolding and aggregation. This research opens the possibility of conducting single molecule molecular folding experiments in quasi‐biological environments.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cytosolic Interactome Protects Against Protein Unfolding in a Single Molecule Experiment

et al. 2023

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“…Contact maps were exported from our custom-made Circuit Topology Python 3 tool. 76 In our CT tool, contacts are identified by means of two cutoffs, one relative to the spatial distance r between atoms (4.5 Å), and one relative to the number of atom pairs that need to be found at a distance less than r to consider the two residues in contact. Contact maps were then processed to extract the contact lifetime distribution of a specific MD run.…”

Section: Methodsmentioning

confidence: 99%

“…Circuit Topology Analysis. Contact maps calculated for specific time regimes were loaded as filters in our CT tool, 76 in order to calculate topological parameters selectively for the chosen dynamic mode. Topological relations are calculated from residue−residue contacts, by assigning an index to contacts based on the order with which the first residue in the contact residue pair appears along the chain, scanning it from left to right.…”

Section: Three-dimensional Structure Prediction Of Nhrmentioning

confidence: 99%

Circuit Topology Approach for the Comparative Analysis of Intrinsically Disordered Proteins

Scalvini

Sheikhhassani

Brug

et al. 2023

J. Chem. Inf. Model.

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Intrinsically disordered proteins (IDPs) lack a stable native conformation, making it challenging to characterize their structure and dynamics. Key topological motifs with fundamental biological relevance are often hidden in the conformational noise, eluding detection. Here, we develop a circuit topology toolbox to extract conformational patterns, critical contacts, and timescales from simulated dynamics of intrinsically disordered proteins. We follow the dynamics of IDPs by providing a smart lowdimensionality representation of their three-dimensional (3D) configuration in the topology space. Such an approach allows us to quantify topological similarity in dynamic systems, therefore providing a pipeline for structural comparison of IDPs.

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Phosphorylation regulated conformational diversity and topological dynamics of an intrinsically disordered nuclear receptor

Akulov,

Panizo,

Estébanez-Perpiñá

et al. 2024

Preprint

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Site-specific phosphorylation of disordered proteins is often considered as a marker of protein activity, yet it is unclear how phosphorylation alters conformational dynamics of disordered protein chains, such as those in the nuclear receptor superfamily. In the case of disordered human glucocorticoid receptor N-terminal domain (GR NTD), a negatively charged region known as core activation function 1 (AF1c) features three phosphorylation sites, regulating its function and intracellular localization. Deletion of this sequence reduces GR transcriptional activation ability dramatically in cell experiments. By developing a circuit topology-based fold analysis approach, combined with atomistic simulations, we reveal that site-specific phosphorylation facilitates formation of non-local contacts, leading to the emergence of disordered compact topologies with significant entanglement, which are distinct from solvent exposed topologies. While we observe that the topological buildup of solvent-exposed states is similar in different phosphovariants, it depends on the exact phosphorylation site for the disordered compact states. This study thus reveals the complex regulatory role of the GR phosphorylation and introduces a unique analysis framework that can be broadly applied to studying topological dynamics of disordered proteins.

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ProteinCT: An implementation of the protein circuit topology framework

Cited by 5 publications

References 25 publications

Cytosolic Interactome Protects Against Protein Unfolding in a Single Molecule Experiment

Cytosolic Interactome Protects Against Protein Unfolding in a Single Molecule Experiment

Circuit Topology Approach for the Comparative Analysis of Intrinsically Disordered Proteins

Phosphorylation regulated conformational diversity and topological dynamics of an intrinsically disordered nuclear receptor

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