On the Accuracy of Transmembrane Segment Prediction of Helical Integral Membrane Proteins

Abstract

Integral membrane proteins play a vital role in a number of essential biological functions. Although abundant, about 30% of genes are known to code for membrane proteins, the number of solved structures in the pdb is less than 1%. Thus, structure prediction of membrane proteins is an essential tool for understanding their functions. A fundamental characteristic of the predicted structure is the topology – identification of trans-membrane segments and the overall orientation with respect to the membrane (intraor extra-cellular). Several prediction methods have been developed for this purpose, both knowledge-based and residue hydrophobicity-based. Although the performances of almost all of these methods are rather high, short loops and long helices are predicted less accurately [1]. One of the problems of estimating accuracy of different prediction methods is the absence of experimentally reliable trans-membrane annotations to compare with. Thus, one is forced to compare prediction versus prediction, where the assumed transmembrane segments typically are identical to entire helix lengths of putative membrane-spanning segments in the pdb structure. Adding hydrophobicity information to the structural data, and by optimizing the resulting membrane-protein mismatch energy, we provide alternate assignments of trans-membrane segments of membrane proteins whose structures are known. This new assignment is used to revaluate the prediction accuracy of established prediction methods and hydrophobicity-based methods. The implications of our results are discussed.