title: mCSM: predicting the effects of mutations in proteins using graph-based signatures.
abstract: BACKGROUND
  Mutations play fundamental roles in evolution by introducing diversity into genomes. Missense mutations in structural genes may become either selectively advantageous or disadvantageous to the organism by affecting protein stability and/or interfering with interactions between partners. Thus, the ability to predict the impact of mutations on protein stability and interactions is of significant value, particularly in understanding the effects of Mendelian and somatic mutations on the progression of disease. Here, we propose a novel approach to the study of missense mutations, called mCSM, which relies on graph-based signatures. These encode distance patterns between atoms and are used to represent the protein residue environment and to train predictive models. To understand the roles of mutations in disease, we have evaluated their impacts not only on protein stability but also on protein-protein and protein-nucleic acid interactions.
  
  
  RESULTS
  We show that mCSM performs as well as or better than other methods that are used widely. The mCSM signatures were successfully used in different tasks demonstrating that the impact of a mutation can be correlated with the atomic-distance patterns surrounding an amino acid residue. We showed that mCSM can predict stability changes of a wide range of mutations occurring in the tumour suppressor protein p53, demonstrating the applicability of the proposed method in a challenging disease scenario.
  
  
  METHODS
  A web server is available at http://structure.bioc.cam.ac.uk/mcsm.
authors.affiliation: Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, UK and ACRF Rational Drug Discovery Centre and Biota Structural Biology Laboratory, St Vincents Institute of Medical Research, Fitzroy, VIC, 3065, Australia.
authors.forename: Douglas E V
authors.initials: DE
authors.lastname: Pires
authors.forename: David B
authors.initials: DB
authors.lastname: Ascher
authors.forename: Tom L
authors.initials: TL
authors.lastname: Blundell
mesh_terms: D000465:Algorithms; D000596:Amino Acids / Q000737:chemistry; D003196:Computer Graphics; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D046912:Multiprotein Complexes / Q000235:genetics; D020125:Mutation, Missense; D055550:Protein Stability; D011506:Proteins / Q000737:chemistry / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D000596:Amino Acids; D004268:DNA-Binding Proteins; D046912:Multiprotein Complexes; D011506:Proteins; D016159:Tumor Suppressor Protein p53; D004247:DNA