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 pr oteins. However since transmembrane regions of a protein are in a distinctl y different environment than globular proteins, one would expect generalize d substitution matrices to be inappropriate for transmembrane regions. Results: We present the PHAT (predicted hydrophobic and transmembrane) matr ix, which significantly outperforms generalized matrices and a previously p ublished transmembrane matrix in searches with transmembrane queries. We co nclude that a better matrix can be constructed by using background frequenc ies characteristic of the twilight zone, where low-scoring true positives h ave scores indistinguishable from high-scoring false positives, rather than the amino acid frequencies of the database. The PHAT matrix may help impro ve the accuracy of sequence alignments and evolutionary trees of membrane p roteins.