Mechismo: predicting the mechanistic impact of mutations and modifications on molecular interactions.
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.
Cell Networks, University of Heidelberg, Im Neuenheimer Feld 267, 69120 Heidelberg, Germany Bioquant, University of Heidelberg, Im Neuenheimer Feld 267, 69120 Heidelberg, Germany.
Matthew J
MJ
Betts
Cell Networks, University of Heidelberg, Im Neuenheimer Feld 267, 69120 Heidelberg, Germany Bioquant, University of Heidelberg, Im Neuenheimer Feld 267, 69120 Heidelberg, Germany.
Qianhao
Q
Lu
Cell Networks, University of Heidelberg, Im Neuenheimer Feld 267, 69120 Heidelberg, Germany Bioquant, University of Heidelberg, Im Neuenheimer Feld 267, 69120 Heidelberg, Germany.
YingYing
Y
Jiang
Cell Networks, University of Heidelberg, Im Neuenheimer Feld 267, 69120 Heidelberg, Germany Bioquant, University of Heidelberg, Im Neuenheimer Feld 267, 69120 Heidelberg, Germany.
Armin
A
Drusko
Cell Networks, University of Heidelberg, Im Neuenheimer Feld 267, 69120 Heidelberg, Germany Bioquant, University of Heidelberg, Im Neuenheimer Feld 267, 69120 Heidelberg, Germany.
Oliver
O
Wichmann
Cell Networks, University of Heidelberg, Im Neuenheimer Feld 267, 69120 Heidelberg, Germany Bioquant, University of Heidelberg, Im Neuenheimer Feld 267, 69120 Heidelberg, Germany.
Mathias
M
Utz
Cell Networks, University of Heidelberg, Im Neuenheimer Feld 267, 69120 Heidelberg, Germany Bioquant, University of Heidelberg, Im Neuenheimer Feld 267, 69120 Heidelberg, Germany.
Ilse A
IA
Valtierra-Gutiérrez
Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
Matthias
M
Schlesner
Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
Natalie
N
Jaeger
Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
David T
DT
Jones
Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
Stefan
S
Pfister
Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
Peter
P
Lichter
Bioquant, University of Heidelberg, Im Neuenheimer Feld 267, 69120 Heidelberg, Germany Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany Department for Bioinformatics and Functional Genomics, Institute for Pharmacy and Molecular Biotechnology (IPMB), University of Heidelberg, Heidelberg, Germany.
Roland
R
Eils
Institut für Humangenetik, Universitätsklinikum Schleswig-Holstein, Christian-Albrechts-Universität zu Kiel, Arnold Heller Straße 3, 24105 Kiel, Germany.
Reiner
R
Siebert
EMBL, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
Peer
P
Bork
Cell Networks, University of Heidelberg, Im Neuenheimer Feld 267, 69120 Heidelberg, Germany Bioquant, University of Heidelberg, Im Neuenheimer Feld 267, 69120 Heidelberg, Germany Cambridge Cell Networks Ltd, St John's Innovation Centre, Cowley Road, CB3 0WS, Cambridge, UK.
Gordana
G
Apic
EMBL, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
Anne-Claude
AC
Gavin
Cell Networks, University of Heidelberg, Im Neuenheimer Feld 267, 69120 Heidelberg, Germany Bioquant, University of Heidelberg, Im Neuenheimer Feld 267, 69120 Heidelberg, Germany robertbrucerussell@gmail.com.
Robert B
RB
Russell
D030562:Databases, Protein; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000235:genetics; D011487:Protein Conformation; D025941:Protein Interaction Mapping; D011506:Proteins / Q000235:genetics*; D040901:Proteomics
D011506:Proteins