  We report a 3D structure-based method of predicting protein-protein
interaction partners. It involves screening for pairs of tetrahedra
representing interacting amino acids at the interface of the protein-protein
complex, with one tetrahedron on each protomer. H-bonds and VDW interactions at
their interface are first determined and then interacting tetrahedral motifs
(one from each protomer) representing backbone or side chain centroids of the
interacting amino acids, are then built. The method requires that the protein
protomers be transformed first into double-centroid reduced representation
(Reyes, V.M. & Sheth, V.N., 2011; Reyes, V.M., 2015a). The method is applied to
a set of 801 protein structures in the PDB with unknown functions, which were
screened for pairs of tetrahedral motifs characteristic of nine binary
complexes, namely: (1.) RAP-Gmppnp-cRAF1 Ras-binding domain; (2.) RHOA-protein
kinase PKN/PRK1 effector domain; (3.) RAC-HOGD1; (4.) RAC-P67PHOX; (5.)
kinase-associated phosphatase (KAP)-phosphoCDK2; (6.) Ig Fc-protein A fragment
B; (7.) Ig light chain dimers; (8.) beta catenin-HTCF-4; and (9.) IL-2
homodimers. Our search method found 33, 297, 62, 63, 120, 0, 108, 16 and 504
putative complexes, respectively. After considering the degree of interface
overlap between the protomers, these numbers were significantly trimmed down to
4, 2, 1, 8, 3, 0, 1, 1 and 1, respectively. Negative and positive control
experiments indicate that the screening process has acceptable specificity and
sensitivity. The results were further validated by applying the CP and TS
methods (Reyes, V.M., 2015b) for the quantitative determination of interface
burial and inter-protomer overlap in the complex. Our method is simple, fast
and scalable, and once the partner interface 3D SMs are identified, they can be
used to computationally dock the two protomers together to form the complex.
