Membrane topology

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Topology of a transmembrane protein refers to orientations (locations of N- and C-termini) of membrane-spanning segments with respect to the inner or outer sides of the biological membrane occupied by the protein.[1][2]

Several databases provide experimentally determined topologies of membrane proteins. They include Uniprot, TOPDB,[3][4][5] OPM, and ExTopoDB.[6][7] There is also a database of domains located conservatively on a certain side of membranes, TOPDOM.[8]

Several computational methods were developed, with a limited success, for predicting transmembrane alpha-helices and their topology. Pioneer methods utilized the fact that membrane spanning regions contain more hydrophobic residues than other parts of the protein, however applying different hydrophobic scales altered the prediction results. Later several statistical method was developed to improve the topography prediction, as well as a special alignment method was introduced.[9] According to the positive-inside rule,[10] cytoslic loops near the lipid bilayer contain more positively charged amino acids. Applying this information resulted in the first topology prediction methods. As more structures were determined, machine learning algorithms appeared. Supervised learning methods are trained on a set of experimentally determined structures, however these methods highly depend on the training set used.[11][12][13][14] Unsupervised learning methods are based on the principle that topology depends on the maximum divergence of the amino acid distributions in different structural parts.[15][16] It was also shown that locking a segment location based on prior knowledge about the structure improves the prediction accuracy.[17] This feature has been added to some of the existing prediction methods.[18][19] The most recent methods use consensus prediction (i.e. they use several algorithm to determine the final topology) [20] and automatically incorporate previously determined experimental informations.[21] HTP database[22][23] provides a collection of topologies that are computationally predicted for human transmembrane proteins.

Discrimination of hydrophobic signal peptides and transmembrane segments is an additional problem in topology prediction treated with a limited success by different methods.[24]

It is also possible to predict beta-barrel membrane proteins' topology.[25]

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