Structural space of protein–protein interfaces is degenerate, close to complete, and highly connected

Abstract

At the heart of protein-protein interactions are protein-protein interfaces where the direct physical interactions occur. By developing and applying an efficient structural alignment method, we study the structural similarity of representative protein-protein interfaces involving interactions between dimers. Even without structural similarity between individual monomers that form dimeric complexes, ∼90% of native interfaces have a close structural neighbor with similar backbone C α geometry and interfacial contact pattern. About 80% of the interfaces form a dense network, where any two interfaces are structurally related using a transitive set of at most seven intermediate interfaces. The degeneracy of interface space is largely due to the packing of compact, hydrogen-bonded secondary structure elements. This packing generates relatively flat interacting surfaces whose geometries are highly degenerate. Comparative study of artificial and native interfaces argues that the library of protein interfaces is close to complete and comprised of roughly 1,000 distinct interface types. In contrast, the number of possible quaternary structures of dimers is estimated to be about 10 4 times larger; thus, an experimentally determined database of all representative quaternary structures is not likely in the near future. Nevertheless, one could in principle exploit the completeness of protein interfaces to predict most dimeric quaternary structures. Finally, our results provide a structural explanation for the prevalence of promiscuous protein interactions. By side-chain packing adjustments, we illustrate how multiprotein specificity can be attained at a promiscuous interface.

Are protein-protein interfaces special regions on a protein’s surface?

“…The sequence similarity score between the HI of query "i" and its template is calculated using the following equation: (9) in which N intf is the total number of amino acids in the HI of the query and s j is the similarity score between the amino acid " j" in the query and the corresponding amino acid in the HI of the template " j ′ ." The value of s j equals one or zero if the BLOSUM62 50 element for jj ′ is greater than zero or less than or equal to zero, respectively.…”

The distribution of ligand-binding pockets around protein-protein interfaces suggests a general mechanism for pocket formation

“…Protein interfaces are usually large, with a buried solvent accessible area of over 1;000 Å 2 (3). With the exception of intertwined interface structures, most protein interfaces have planar shapes (4,9,10). Although there are in principle millions of ways of forming protein-protein interfaces, a recent study has revealed that the structural space of protein interfaces is surprisingly small, primarily attributed to limited ways of protein secondary structural packing and the flatness of interfaces (10).…”

“…Artificial protein-protein interfaces were extracted from previously built artificial protein complexes (10). These artificial complexes were originally taken from a library of polyvaline structures generated with the protein structure prediction package TASSER (40).…”

“…These artificial complexes were originally taken from a library of polyvaline structures generated with the protein structure prediction package TASSER (40). They were then converted to all-atom models using random protein sequences (10). From these structures, a total of 2,000 pairs of artificial structures were randomly chosen and rigid-body docking was subsequently conducted with FT-dock (41).…”

“…Since artificial complex structures have a size limit of 600 amino acids, we chose 363 native complexes within this size limit that are bound to at least one ligand for the comparative pocket analysis. For each native complex, we selected a unique artificial structure that has the best interface similarity according nonsequential alignment by the program iAlign (10,27), yielding a total set of 363 artificial complexes for pocket analysis.…”