Recently, Fernández and Lynch 
showed that random genetic drift is the chief driving force behind thermodynamically less stable yet densely interacting proteins in higher organisms 
. Additionally, protein complexes in higher organisms have more members than in lower organisms 
. Recently, it was observed that a destabilizing mutation in the enzyme DHFR in E. coli
leads to functional tetramerization of the otherwise monomeric enzyme 
suggesting that protein-protein interactions can at least partially compensate the effect of protein destabilization.
lactoglobulin is an aggregation-prone protein generally found as a dimer. It was shown that the specific interactions responsible for the formation of the dimer considerably reduce the risk of protein aggregation 
. Ataxin-3 is a protein implicated in polyglutamine expansion diseases wherein the functional interactions of the protein reduce the exposure of its aggregation prone interface and thereby decrease its aggregation propensity 
Here, we have quantified the interaction-induced stability on a proteome wide scale and hypothesized that the PPI-induced stabilization is a secondary evolutionary advantage of the PPI network; alleviating the selection pressure on proteins in functional multi-protein complexes to evolve a stable folded. A simple model for the fitness of the proteome provided a fundamental justification for the co-evolution of protein stability and protein-protein interactions and made predictions that were tested on the proteome of baker's yeast. In the model, when the effects of natural selection are weak, proteins acquire stability mainly via protein-protein interactions. At a higher population size — in the absence of genetic drift — proteins are intrinsically stable and protein-protein interactions stabilize only those proteins that fail to evolve inherent stability.
We have also presented evidence that all
interacting proteins stabilize their binding partners to a certain extent and act as the evolutionary capacitance 
for their evolution. Interestingly, though some of the top 20 capacitors predicted in this study are known chaperones and are over-represented in GO ontology terms such as protein binding
, unfolded protein binding
, and protein folding
; others do not have any protein folding-related functional annotation and need experimental investigation.
The importance of disordered proteins, especially in the proteomes of higher organisms, cannot be neglected. The proteome of baker's yeast does not have many completely disordered proteins but
of the amino acids in the proteins of yeast are predicted to be in a disordered state 
for the proteins considered in this study, see supplementary Text S1
and Fig. S4
). Even though the development presented above applied only to an equilibrium between folded and unfolded/misfolded/aggregated protein, it can be easily generalized to disordered proteins. This is because even though the folded
unfolded equilibrium is not well defined, similar to well structured proteins, disordered proteins also exist either in a soluble monomeric (instead of the folded state), a misfolded/aggregated, and a complexed state. Many disordered proteins acquire a definite structure when bound to their interaction partners and seldom dissociate to the soluble monomeric 
. These serve as even stronger candidates for the beneficiaries of interaction-induced stability compared to folded proteins. Consequently, we include both partially disordered proteins and structured proteins in the current analysis of the
Suggested experimental tests
Modulation of protein stability by overexpression of its partners
We predict that the measured free energy of protein folding in vivo 
will be lower than the in vitro measurement. Moreover, this free energy can be modulated by overexpressing the interaction partners of the protein that increases the equilibrium constant
between the folded monomer and the generic complexed state. Recently, it was observed that the measured stability of phosphoglycerate kinase was higher by
compared to in vitro
Does the PPI-induced stabilization have evolutionary advantages? We propose the following experimental test. Consider two mutated phenotypes for an isolated interacting pair of proteins A and B in an organism 1)
, a destabilized mutant of protein A and 2)
where B is overexpressed. We predict that lowering of the organismal fitness due to destabilization of protein A (
) can be at least partially rescued by the overexpression of the protein B (
) i.e. the combination of two penalizing mutations may perhaps be advantageous to the organism.