Physics and Evolution of Protein‐Protein Interactions

We will discuss recent developments in bioinformatics analysis and theoretical studies of protein‐protein interactions in living cells – an important aspect of systems biology. First, we consider the network of protein‐protein interactions and demonstrate that two published independent measurements of these interactions produce graphs that are only weakly correlated with one another despite their strikingly similar topology. We then propose a physical model based on the fundamental principle that (de)solvation is a major physical factor in protein‐protein interactions. This model reproduces not only the scale‐free nature of such graphs but also a number of higher‐order correlations in these networks. A key support of the model is provided by the discovery of a significant correlation between number of interactions made by a protein and the fraction of hydrophobic residues on its surface. Next, we discuss a number of fundamental models for specific protein‐protein interactions that provide deep insight into how specific protein multimers could have evolved. In particular we show that homodimers are most likely to have been precursors of modern protein complexes (homodimers are prevalent in modern cells – phenomenon of “molecular narcissism”). Subsequent evolution created homodimers in the process of ‘'negative design’’ against non‐specific and homodimeric associations.