Predicting transmembrane helix pair configurations with knowledge-based distance-dependent pair potentials

As a first step toward a novel de novo structure prediction approach for alpha-helical membrane proteins, we developed coarse-grained knowledge-based potentials to score the mutual configuration of transmembrane (TM) helices. Using a comprehensive database of 71 known membrane protein structures, pairwise potentials depending solely on amino acid types and distances between C(alpha)-atoms were derived. To evaluate the potentials, they were used as an objective function for the rigid docking of 442 TM helix pairs. This is by far the largest test data set reported to date for that purpose. After clustering 500 docking runs for each pair and considering the largest cluster, we found solutions with a root mean squared (RMS) deviation <2 A for about 30% of all helix pairs. Encouragingly, if only clusters that contain at least 20% of all decoys are considered, a success rate >71% (with a RMS deviation <2 A) is obtained. The cluster size thus serves as a measure of significance to identify good docking solutions. In a leave-one-protein-family-out cross-validation study, more than 2/3 of the helix pairs were still predicted with an RMS deviation <2.5 A (if only clusters that contain at least 20% of all decoys are considered). This demonstrates the predictive power of the potentials in general, although it is advisable to further extend the knowledge base to derive more robust potentials in the future. When compared to the scoring function of Fleishman and Ben-Tal, a comparable performance is found by our cross-validated potentials. Finally, well-predicted "anchor helix pairs" can be reliably identified for most of the proteins of the test data set. This is important for an extension of the approach towards TM helix bundles because these anchor pairs will act as "nucleation sites" to which more helices will be added subsequently, which alleviates the sampling problem.