An optimal distance cutoff for contact-based Protein Structure Networks using side-chain centers of mass

Viloria, Juan Salamanca; Allega, Maria Francesca; Lambrughi, Matteo; Papaleo, Elena

doi:10.1038/s41598-017-01498-6

Cited by 79 publications

(66 citation statements)

References 75 publications

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“…Distance cutoffs between 4-6Å are routinely used when examining interactions between proteins or protein-ligand pairs as most noncovalent atomic interactions are short-range (e.g., hydrogen bonds and Van der Waals interaction range from 3-4Å (Esmaielbeiki et al, 2016;Lodish et al, 2000)). For instance, a recent study on contact-based protein structure networks by Viloria and colleagues found that a distance cutoff of <5Å (heavy atoms) is most sensitive to changes in residue interactions and variables such as force fields (Salamanca Viloria et al, 2017). Therefore, we defined paratope-epitope interacting residues by a distance cutoff of <5Å between heavy atoms, i.e., amino acid residues are interacting if they have heavy atoms with a distance <5Å from each other ( Fig.…”

Section: Definition Of Interacting Residues In Antibody-antigen Complmentioning

confidence: 99%

A compact vocabulary of paratope-epitope interactions enables predictability of antibody-antigen binding

Akbar

Jeliazkov

Robert

et al. 2019

Preprint

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Antibody recognition of antigen relies on the specific interaction of amino acids at the paratopeepitope interface. A long-standing question in the fields of immunology and structural biology is whether paratope-epitope interaction is predictable. A fundamental premise for the predictability of paratope-epitope binding is the existence of structural units that are universally shared among antibody-antigen binding complexes. Here, we identified structural interaction motifs, which together compose a vocabulary of paratope-epitope binding that is shared among investigated antibody-antigen complexes. The vocabulary (i) is finite with less than 10 4 motifs, (ii) mediates specific and non-redundant interactions between paratope-epitope pairs, (iii) is immunity-specific (distinct from the motif vocabulary used by non-immune protein-protein interactions), and (iv) enables the machine learning prediction of paratope or epitope. The discovery of a vocabulary of paratope-epitope interaction demonstrates the learnability and predictability of paratope-epitope interaction.

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Section: Definition Of Interacting Residues In Antibody-antigen Complmentioning

confidence: 99%

A compact vocabulary of paratope-epitope interactions enables predictability of antibody-antigen binding

Akbar

Jeliazkov

Robert

et al. 2019

Preprint

View full text Add to dashboard Cite

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“…We recently applied it to the study of other cancer-related proteins, allowing to shed light on the underlying structural communication among distal sites Lambrughi et al, 2016;Papaleo et al, 2012a;Sora and Papaleo, 2019) or to help in the classification of potential cancer passenger and driver missense mutations (Nygaard et al, 2016). In details, the PSN employs the graph formalism to identify a network of interacting residues in a given protein from the number of non-covalent contacts in the protein or other intramolecular interactions Viloria et al, 2017). Two main properties of a PSN are the hub residues, i.e., residues that are highly connected within the network and the connected components, i.e., clusters of residues which are inter-connected but do not interact with residues in other clusters.…”

Section: Lc3b Ensemble Under the Lens Of Protein Structure Network: Hmentioning

confidence: 99%

“…On the contrary, if hubs are altered, the network integrity can be compromised. We calculated three PSNs, based on sidechain contacts Viloria et al, 2017), hydrogen bonds and salt-bridges (Jónsdóttir et al, 2014;Tiberti et al, 2014), respectively. We then calculated the hubs and connected components from the contact-based and hydrogen-bond based PSNs from the CHARMM22* simulation of LC3B.…”

Section: Lc3b Ensemble Under the Lens Of Protein Structure Network: Hmentioning

confidence: 99%

“…For the contact-based PSN, we tested four different distance cutoffs to define the existence of a link between the nodes (i.e., 5, 5.125, 5.25 and 5.5 Å). Then we selected the cutoff of 5.125 Å as the best compromise between an entirely connected and a sparse network, according to our recent work on PSN cutoffs (Viloria et al, 2017). The distance was estimated between the center of mass of the residues side chains (expect glycines).…”

Section: Network Analyses Of the MD Ensemblesmentioning

confidence: 99%

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The conformational and mutational landscape of the ubiquitin-like marker for the autophagosome formation in cancer

Fas

Kumar

Sora

et al. 2019

Preprint

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Autophagy is a cellular process to recycle damaged cellular components and its modulation can be exploited for disease treatments. A key autophagy player is a ubiquitin-like protein, LC3B. Compelling evidence attests the role of autophagy and LC3B in different cancer types. Many LC3B structures have been solved, but a comprehensive study, including dynamics, has not been yet undertaken. To address this knowledge gap, we assessed ten physical models for molecular dynamics for their capabilities to describe the structural ensemble of LC3B in solution using different metrics and comparison with NMR data. With the resulting LC3B ensembles, we characterized the impact of 26 missense mutations from Pan-Cancer studies with different approaches. Our findings shed light on driver or neutral mutations in LC3B, providing an atlas of its modifications in cancer. Our framework could be used to assess the pathogenicity of mutations by accounting for the different aspects of protein structure and function altered by mutational events.

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“…We used the node inter-connectivity to calculate the connected components, which are clusters of connected residues in the graph. We selected 5 Å as the optimal cutoff for the contact-based PSN using the PyInKnife pipeline [87]. The distance was estimated between the center of mass of the residue side chains.…”

Section: Protein Structure Networkmentioning

confidence: 99%

A Pan-Cancer assessment of alterations of the kinase domain of ULK1, an upstream regulator of autophagy

Kumar

Papaleo

2019

Preprint

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Autophagy is a key clearance process for the cell to recycle damaged cellular components. Autophagy is also well known for its dual role in cancer, acting as both tumor suppressor or promoter in a context-dependent way. One important upstream regulator of autophagy is the kinase ULK1. Several structures of the kinase domain of ULK1 have been solved, but a comprehensive study, including molecular dynamics, is currently missing. Also, an exhaustive description of the landscape of ULK1 cancer-related alterations is presently lacking. We here exploited the large amount of data on more than 30 cancer types through The Cancer Genome Atlas and the Recount2 initiatives to identify and analyze the atlas of ULK1 alterations in terms of gene expression and mutations. Moreover, we predicted the effects of mutations on ULK1 function and structural stability using a computational workflow accounting for protein dynamics and different layers of changes that a mutation can induce in a protein.We discovered that ULK1, along with ULK2 are down-regulated in gynecological tumors, suggesting an impairment of the upstream regulation of autophagy. In other cancer types, ULK2 can compensate for ULK1 downregulation and, in the majority of the cases, no marked changes in expression level have been found for both genes. We identified 36 missense mutations of ULK1 especially in uterine, colon, stomach and lung cancer that were co-occurring with mutations in a large number of ULK1 interactors, suggesting a pronounced effect of the upstream steps of autophagy in these cancer types. Moreover, our study allowed to pinpoint that more than 50% of the mutations of ULK1 found in the cancer samples affect protein stability, which is likely to affect the cellular level and turnover of the protein. Among the damaging mutations for stability, A125T, F273V, L215P, F14L, and G12D are also predicted not to alter the functional state of the protein. Three mutations (S184F, D102N, and A28V) are predicted with the only impact on kinase activity, either modifying the functional dynamics of the protein or the capability to exert effects from distal site to the functional and catalytic regions. The framework here applied could be extended more broadly to other targets to help in the classification of mutational effects in disease, to prioritize variants for experimental validation or select the appropriate biological readouts for experiments.suggested to play essential scaffolding roles for autophagosome formation and maturation [9]. ULK1 has been reported overexpressed or downregulated in different cancer types or subtypes [25][26][27][28]. Autophagy in general has a strong association with cancer and can act with a dual role in a context-dependent way, being both tumor suppressor or promoter [29,30]. AMPK-ULK1 mediated autophagy also induces resistance against bromodomain and extraterminal domain inhibitors, which are novel epigenetic therapeutics for acute myeloid leukemia [31].So it can be a pivotal target to curb the chemotherapeutic resistance in cancers....

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An optimal distance cutoff for contact-based Protein Structure Networks using side-chain centers of mass

Cited by 79 publications

References 75 publications

A compact vocabulary of paratope-epitope interactions enables predictability of antibody-antigen binding

A compact vocabulary of paratope-epitope interactions enables predictability of antibody-antigen binding

The conformational and mutational landscape of the ubiquitin-like marker for the autophagosome formation in cancer

A Pan-Cancer assessment of alterations of the kinase domain of ULK1, an upstream regulator of autophagy

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