Abstract

We introduce ZEPPI (Z-score Evaluation of Protein–Protein Interfaces), a framework to evaluate structural models of a complex based on sequence coevolution and conservation involving residues in protein–protein interfaces. The ZEPPI score is calculated by com- paring metrics for an interface to those obtained from randomly chosen residues. Since contacting residues are defined by the structural model, this obviates the need to account for indirect interactions. Further, although ZEPPI relies on species-paired multiple sequence alignments, its focus on interfacial residues allows it to leverage quite shallow alignments. ZEPPI can be implemented on a proteome-wide scale and is applied here to millions of structural models of dimeric complexes in the Escherichia coli and human interactomes found in the PrePPI database. PrePPI’s scoring function is based primarily on the evalua- tion of protein–protein interfaces, and ZEPPI adds a new feature to this analysis through the incorporation of evolutionary information. ZEPPI performance is evaluated through applications to experimentally determined complexes and to decoys from the CASP-CAPRI experiment. As we discuss, the standard CAPRI scores used to evaluate docking models are based on model quality and not on the ability to give yes/no answers as to whether two proteins interact. ZEPPI is able to detect weak signals from PPI models that the CAPRI scores define as incorrect and, similarly, to identify potential PPIs defined as low confidence by the current PrePPI scoring function. A number of examples that illustrate how the combination of PrePPI and ZEPPI can yield functional hypotheses are provided.