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Environment specific substitution tables improve membrane protein alignment.

Hill JR, Kelm S, Shi J, Deane CM - Bioinformatics (2011)

Bottom Line: 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.Our alignments also lead to improved structural models.

View Article: PubMed Central - PubMed

Affiliation: Department of Statistics, University of Oxford, 1 South Parks Road, Oxford, OX1 3TG, UK.

ABSTRACT

Motivation: 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.

Availability: Substitution tables are available at: http://www.stats.ox.ac.uk/proteins/resources.

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Related in: MedlinePlus

A high-quality table (IHA, a) and low-quality table (TPa, b). Each point is the fraction of total counts and consistency of a table when constructed with 20 more alignments than the preceding point. Some points are superimposed.
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Figure 2: A high-quality table (IHA, a) and low-quality table (TPa, b). Each point is the fraction of total counts and consistency of a table when constructed with 20 more alignments than the preceding point. Some points are superimposed.

Mentions: The self-consistency score is scale-invariant, so it provides a measure of table quality that is independent of the number of counts. Figure 2 shows a useful scheme for visually identifying poor tables. The fraction of the total number of counts and Q are plotted for each table with increasingly large subsets of the data. A stable counts matrix should tend to a stable level of Q as more data is included.Fig. 2.


Environment specific substitution tables improve membrane protein alignment.

Hill JR, Kelm S, Shi J, Deane CM - Bioinformatics (2011)

A high-quality table (IHA, a) and low-quality table (TPa, b). Each point is the fraction of total counts and consistency of a table when constructed with 20 more alignments than the preceding point. Some points are superimposed.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3117371&req=5

Figure 2: A high-quality table (IHA, a) and low-quality table (TPa, b). Each point is the fraction of total counts and consistency of a table when constructed with 20 more alignments than the preceding point. Some points are superimposed.
Mentions: The self-consistency score is scale-invariant, so it provides a measure of table quality that is independent of the number of counts. Figure 2 shows a useful scheme for visually identifying poor tables. The fraction of the total number of counts and Q are plotted for each table with increasingly large subsets of the data. A stable counts matrix should tend to a stable level of Q as more data is included.Fig. 2.

Bottom Line: 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.Our alignments also lead to improved structural models.

View Article: PubMed Central - PubMed

Affiliation: Department of Statistics, University of Oxford, 1 South Parks Road, Oxford, OX1 3TG, UK.

ABSTRACT

Motivation: 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.

Availability: Substitution tables are available at: http://www.stats.ox.ac.uk/proteins/resources.

Show MeSH
Related in: MedlinePlus