PHAT: a transmembrane-specific substitution matrix

Motivation: Database searching algorithms for proteins use scoring matrices based on average protein properties, and thus are dominated by globular proteins. However since transmembrane regions of a protein are in a distinctly different environment than globular proteins, one would expect generalized substitution matrices to be inappropriate for transmembrane regions. Results: We present the PHAT (predicted hydrophobic and transmembrane) matrix, which significantly outperforms generalized matrices and a previously published transmembrane matrix in searches with transmembrane queries. We conclude that a better matrix can be constructed by using background frequencies characteristic of the twilight zone, where low-scoring true positives have scores indistinguishable from high-scoring false positives, rather than the amino acid frequencies of the database. The PHAT matrix may help improve the accuracy of sequence alignments and evolutionary trees of membrane proteins.