title: Environment specific substitution tables improve membrane protein alignment.
abstract: BACKGROUND
  Membrane proteins are both abundant and important in cells, but the small number of solved structures restricts our understanding of them. Here we consider whether membrane proteins undergo different substitutions from their soluble counterparts and whether these can be used to improve membrane protein alignments, and therefore improve prediction of their structure.
  
  
  RESULTS
  We construct substitution tables for different environments within membrane proteins. As data is scarce, we develop a general metric to assess the quality of these asymmetric tables. Membrane proteins show markedly different substitution preferences from soluble proteins. For example, substitution preferences in lipid tail-contacting parts of membrane proteins are found to be distinct from all environments in soluble proteins, including buried residues. A principal component analysis of the tables identifies the greatest variation in substitution preferences to be due to changes in hydrophobicity; the second largest variation relates to secondary structure. We demonstrate the use of our tables in pairwise sequence-to-structure alignments (also known as 'threading') of membrane proteins using the FUGUE alignment program. On average, in the 10-25% sequence identity range, alignments are improved by 28 correctly aligned residues compared with alignments made using FUGUE's default substitution tables. Our alignments also lead to improved structural models.
  
  
  BACKGROUND
  Substitution tables are available at: http://www.stats.ox.ac.uk/proteins/resources.
authors.affiliation: Department of Statistics, University of Oxford, 1 South Parks Road, Oxford, OX1 3TG, UK.
authors.forename: Jamie R
authors.initials: JR
authors.lastname: Hill
authors.forename: Sebastian
authors.initials: S
authors.lastname: Kelm
authors.forename: Jiye
authors.initials: J
authors.lastname: Shi
authors.forename: Charlotte M
authors.initials: CM
authors.lastname: Deane
mesh_terms: D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry*; D008958:Models, Molecular; D025341:Principal Component Analysis; D017433:Protein Structure, Secondary; D016415:Sequence Alignment / Q000379:methods*; D020539:Sequence Analysis, Protein / Q000379:methods*; D012984:Software; D040681:Structural Homology, Protein
chemical_list: D008565:Membrane Proteins