TMB-Hunt: An amino acid composition based method to screen proteomes for beta-barrel transmembrane proteins

We present TMB-Hunt, a program that uses a k-Nearest Neighbour (k-NN) algorithm to discriminate between bbtm and non-bbtm proteins on the basis of their amino acid composition. By including differentially weighted amino acids, evolutionary information and by calibrating the scoring, an accuracy of 92.5% was achieved, with 91% sensitivity and 93.8% positive predictive value (PPV), using a rigorous cross-validation procedure.A major advantage of this approach is that because it does not rely on beta-strand detection, it does not require resolved structures and thus larger, more representative, training sets could be used. It is therefore believed that this approach will be invaluable in complementing other, physicochemical and homology based methods. This was demonstrated by the correct reassignment of a number of proteins which other predictors failed to classify. We have used the algorithm to screen several genomes and have discussed our findings.TMB-Hunt achieves a prediction accuracy level better than other approaches published to date. Results were significantly enhanced by use of evolutionary information and a system for calibrating k-NN scoring. Because the program uses a distinct approach to that of other discriminators and thus suffers different liabilities, we believe it will make a significant contribution to the development of a consensus approach for bbtm protein detection.The beta-barrel is one of only two membrane spanning structural motifs currently identified [1]. It is proven with high resolution structures for many proteins expressed within the outer membranes of gram negative bacteria and is also widely expected for several proteins expressed in the outer membranes of mitochondria [2] and chloroplasts [3]. In addition, the structure of a protein found spanning the outer membrane of Mycobacteria (an acid fast gram positive bacterium) was recently resolved revealing two consecutive membrane spanning beta-barrels [4]. As with alpha-helical transmembra