  Statistical analysis of protein-protein interactions shows anomalously high
frequency of homodimers [Ispolatov, I., et al. (2005) Nucleic Acids Res 33,
3629-35]. Furthermore, recent findings [Wright, C.F., et al. (2005) Nature 438,
878-81] demonstrate that maintaining low sequence identity is a key
evolutionary mechanism that inhibits protein aggregation. Here, we study
statistical properties of interacting protein-like surfaces and predict the
effect of universal, enhanced self-attraction of proteins. The effect
originates in the fact that a pattern self-match between two identical, even
randomly organized interacting protein surfaces is always stronger compared to
the pattern match between two different, promiscuous protein surfaces. This
finding implies an increased probability of homodimer selection in the course
of early evolution. Our simple model of early evolutionary selection of
interacting proteins accurately reproduces the experimental data on homodimer
interface aminoacid compositions. In addition, we predict that heterodimers
evolved from homodimers with the negative design evolutionary pressure applied
against promiscuous homodimer formation. We predict that the anti-homodimer
negative design evolutionary signal is conveyed through the enrichment of
heterodimeric interfaces in polar residues, and most profoundly in glutamic
acid and lysine, which is consistent with experimental findings. We predict
therefore that the negative design against homodimers is the
