kPROT: A knowledge-based scale for the propensity of residue orientation in transmembrane segments. Application to membrane protein structure prediction

Modeling of integral membrane proteins and the prediction of their function al sites requires the identification of transmembrane (TM) segments and the determination of their angular orientations. Hydrophobicity scales predict accurately the location of TM helices, but are less accurate in computing angular disposition. Estimating lipid-exposure propensities of the residues from statistics of solved membrane protein structures has the disadvantage of relying on relatively few proteins. As an alternative, we propose here a scale of knowledge-based Propensities for Residue Orientation in Transmem brane segments (kPROT), derived from the analysis of more than 5000 non-red undant protein sequences. We assume that residues that tend to be exposed t o the membrane are more frequent in TM segments of single-span proteins, wh ile residues that prefer to be buried in the transmembrane bundle interior are present mainly in multispan TMs. The kPROT value for each residue is th us defined as the logarithm of the ratio of its proportions in single and m ultiple TM spans. The scale is refined further by defining it for three dis crete sections of the TM segment; namely, extracellular, central, and intra cellular. The capacity of the kPROT scale to predict angular helical orient ation was compared to that of alternative methods in a benchmark test, usin g a diversity of multi-span cc-helical transmembrane proteins with a solved 3D structure. kPROT yielded an average angular error of 41 degrees, signif icantly lower than that of alternative scales (62 degrees-68 degrees). The new scale thus provides a useful general tool for modeling and prediction o f functional residues in membrane proteins. A WWW server (http://bioinfo.we izmann.ac.il/kPROT) is available for automatic helix orientation prediction with kPROT. (C) 1999 Academic Press.