Robust protein-protein interactions in crowded cellular environments

Eric J. Deeds, Orr Ashenberg, Jaline Gerardin, Eugene I. Shakhnovich*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

66 Scopus citations


The capacity of proteins to interact specifically with one another underlies our conceptual understanding of how living systems function. Systems-level study of specificity in protein-protein interactions is complicated by the fact that the cellular environment is crowded and heterogeneous; interaction pairs may exist at low relative concentrations and thus be presented with many more opportunities for promiscuous interactions compared with specific interaction possibilities. Here we address these questions by using a simple computational model that includes specifically designed interacting model proteins immersed in a mixture containing hundreds of different unrelated ones; all of them undergo simulated diffusion and interaction. We find that specific complexes are quite robust to interference from promiscuous interaction partners only in the range of temperatures T design > T > Trand. At T > Tdesign, specific complexes become unstable, whereas at T < Trand, formation of specific complexes is suppressed by promiscuous interactions. Specific interactions can form only if Tdesign > Trand. This condition requires an energy gap between binding energy in a specific complex and set of binding energies between randomly associating proteins, providing a general physical constraint on evolutionary selection or design of specific interacting protein interfaces. This work has implications for our understanding of how the protein repertoire functions and evolves within the context of cellular systems.

Original languageEnglish (US)
Pages (from-to)14952-14957
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number38
StatePublished - Sep 18 2007


  • Crowded cell environment
  • Promiscuous interactions
  • Specific interactions

ASJC Scopus subject areas

  • General


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