TY - JOUR
T1 - Co-evolving residues in membrane proteins
AU - Fuchs, Angelika
AU - Martin-Galiano, Antonio J.
AU - Kalman, Matan
AU - Fleishman, Sarel
AU - Ben-Tal, Nir
AU - Frishman, Dmitrij
N1 - Funding Information:
This project was supported by the DFG grant ‘A comprehensive analysis of structure-function relationships in membrane protein families’.
PY - 2007/12
Y1 - 2007/12
N2 - Motivation: 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 α-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%.
AB - Motivation: 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 α-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%.
UR - http://www.scopus.com/inward/record.url?scp=36949003878&partnerID=8YFLogxK
U2 - 10.1093/bioinformatics/btm515
DO - 10.1093/bioinformatics/btm515
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AN - SCOPUS:36949003878
SN - 1367-4803
VL - 23
SP - 3312
EP - 3319
JO - Bioinformatics
JF - Bioinformatics
IS - 24
ER -