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Kalinina O.V.,University of Heidelberg | Kalinina O.V.,Max Planck Institute for Informatics | Wichmann O.,University of Heidelberg | Apic G.,University of Heidelberg | And 2 more authors.
Nucleic Acids Research | Year: 2012

Progress in structure determination methods means that the set of experimentally determined 3D structures of proteins in complex with small molecules is growing exponentially. ProtChemSI exploits and extends this useful set of structures by both collecting and annotating the existing data as well as providing models of potential complexes inferred by protein or chemical structure similarity. The database currently includes 7704 proteins from 1803 organisms, 11 324 chemical compounds and 202 289 complexes including 178 974 predicted. It is publicly available at http://pcidb.russelllab.org. © The Author(s) 2011. Published by Oxford University Press.

Betts M.J.,University of Heidelberg | Lu Q.,University of Heidelberg | Jiang Y.,University of Heidelberg | Drusko A.,University of Heidelberg | And 16 more authors.
Nucleic Acids Research | Year: 2015

Systematic interrogation of mutation or protein modification data is important to identify sites with functional consequences and to deduce global consequences from large data sets. Mechismo (mechismo.russellab.org) enables simultaneous consideration of thousands of 3D structures and biomolecular interactions to predict rapidly mechanistic consequences for mutations and modifications. As useful functional information often only comes from homologous proteins, we benchmarked the accuracy of predictions as a function of protein/structure sequence similarity, which permits the use of relatively weak sequence similarities with an appropriate confidence measure. For protein-protein, protein-nucleic acid and a subset of protein-chemical interactions, we also developed and benchmarked a measure of whether modifications are likely to enhance or diminish the interactions, which can assist the detection of modifications with specific effects. Analysis of high-throughput sequencing data shows that the approach can identify interesting differences between cancers, and application to proteomics data finds potential mechanistic insights for how post-translational modifications can alter biomolecular interactions. © 2015 The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.

Kalinina O.V.,University of Heidelberg | Kalinina O.V.,Russian Academy of Sciences | Wichmann O.,University of Heidelberg | Apic G.,University of Heidelberg | And 2 more authors.
PLoS Computational Biology | Year: 2011

Biological networks are powerful tools for predicting undocumented relationships between molecules. The underlying principle is that existing interactions between molecules can be used to predict new interactions. Here we use this principle to suggest new protein-chemical interactions via the network derived from three-dimensional structures. For pairs of proteins sharing a common ligand, we use protein and chemical superimpositions combined with fast structural compatibility screens to predict whether additional compounds bound by one protein would bind the other. The method reproduces 84% of complexes in a benchmark, and we make many predictions that would not be possible using conventional modeling techniques. Within 19,578 novel predicted interactions are 7,793 involving 718 drugs, including filaminast, coumarin, alitretonin and erlotinib. The growth rate of confident predictions is twice that of experimental complexes, meaning that a complete structural drug-protein repertoire will be available at least ten years earlier than by X-ray and NMR techniques alone. © 2011 Kalinina et al.

Apic G.,University of Heidelberg | Apic G.,Cambridge Cell Networks Ltd. | Betts M.J.,University of Heidelberg | Russell R.B.,University of Heidelberg
PLoS ONE | Year: 2011

Indicators that rank countries according socioeconomic measurements are important tools for regional development and political reform. Those currently in widespread use are sometimes criticized for a lack of reproducibility or the inability to compare values over time, necessitating simple, fast and systematic measures. Here, we applied the 'guilt by association' principle often used in biological networks to the information network within the online encyclopedia Wikipedia to create an indicator quantifying the degree to which pages linked to a country are disputed by contributors. The indicator correlates with metrics of governance, political or economic stability about as well as they correlate with each other, and though faster and simpler, it is remarkably stable over time despite constant changes in the underlying disputes. For some countries, changes over a four year period appear to correlate with world events related to conflicts or economic problems. © 2011 Apic et al.

Boldt K.,University of Tubingen | Van Reeuwijk J.,Radboud University Nijmegen | Lu Q.,University of Heidelberg | Koutroumpas K.,Genopole | And 95 more authors.
Nature Communications | Year: 2016

Cellular organelles provide opportunities to relate biological mechanisms to disease. Here we use affinity proteomics, genetics and cell biology to interrogate cilia: poorly understood organelles, where defects cause genetic diseases. Two hundred and seventeen tagged human ciliary proteins create a final landscape of 1,319 proteins, 4,905 interactions and 52 complexes. Reverse tagging, repetition of purifications and statistical analyses, produce a high-resolution network that reveals organelle-specific interactions and complexes not apparent in larger studies, and links vesicle transport, the cytoskeleton, signalling and ubiquitination to ciliary signalling and proteostasis. We observe sub-complexes in exocyst and intraflagellar transport complexes, which we validate biochemically, and by probing structurally predicted, disruptive, genetic variants from ciliary disease patients. The landscape suggests other genetic diseases could be ciliary including 3M syndrome. We show that 3M genes are involved in ciliogenesis, and that patient fibroblasts lack cilia. Overall, this organelle-specific targeting strategy shows considerable promise for Systems Medicine. © 2016, Nature Publishing Group. All rights reserved.

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