Co-evolving residues in membrane proteins.
BACKGROUND
The analysis of co-evolving residues has been exhaustively evaluated for the prediction of intramolecular amino acid contacts in soluble proteins. Although a variety of different methods for the detection of these co-evolving residues have been developed, the fraction of correctly predicted contacts remained insufficient for their reliable application in the construction of structural models. Membrane proteins, which constitute between one-fourth and one-third of all proteins in an organism, were only considered in few individual case studies.


RESULTS
We present the first general study of correlated mutations in alpha-helical membrane proteins. Using seven different prediction algorithms, we extracted co-evolving residues for 14 membrane proteins having a solved 3D structure. On average, distances between correlated pairs of residues lying on different transmembrane segments were found to be significantly smaller compared to a random prediction. Covariation of residues was frequently found in direct sequence neighborhood to helix-helix contacts. Based on the results obtained from individual prediction methods, we constructed a consensus prediction for every protein in the dataset that combines obtained correlations from different prediction algorithms and simultaneously removes likely false positives. Using this consensus prediction, 53% of all predicted residue pairs were found within one helix turn of an observed helix-helix contact. Based on the combination of co-evolving residues detected with the four best prediction algorithms, interacting helices could be predicted with a specificity of 83% and sensitivity of 42%.


BACKGROUND
http://webclu.bio.wzw.tum.de/helixcorr/
Department of Genome Oriented Bioinformatics, Technische Universität München, Wissenschaftszentrum Weihenstephan, 85350 Freising, Germany.
Angelika
A
Fuchs
Antonio J
AJ
Martin-Galiano
Matan
M
Kalman
Sarel
S
Fleishman
Nir
N
Ben-Tal
Dmitrij
D
Frishman
D019943:Amino Acid Substitution; D000596:Amino Acids / Q000737:chemistry* / Q000235:genetics*; D004252:DNA Mutational Analysis / Q000379:methods*; D019143:Evolution, Molecular; D008565:Membrane Proteins / Q000737:chemistry* / Q000235:genetics*; D016415:Sequence Alignment / Q000379:methods; D020539:Sequence Analysis, Protein / Q000379:methods*; D017385:Sequence Homology
D000596:Amino Acids; D008565:Membrane Proteins