Robust protein–protein interactions in crowded cellular environments

doi:10.1073/pnas.0702766104

Robust protein–protein interactions in crowded cellular environments

^†Department of Systems Biology, Harvard Medical School, 200 Longwood Avenue, Warren Alpert #536, Boston, MA 02115;
^‡Computational and Systems Biology Program, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Building 68, Cambridge, MA 02139;
^§Harvard College, 12 Oxford Street, Cambridge, MA 02138; and
^¶Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA 02138

Edited by William A. Eaton, National Institutes of Health, Bethesda, MD, and approved July 30, 2007 (received for review March 23, 2007)

Abstract

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 > T _rand. At T > T _design, specific complexes become unstable, whereas at T < T _rand, formation of specific complexes is suppressed by promiscuous interactions. Specific interactions can form only if T _design > T _rand. 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.

Footnotes

^‖To whom correspondence should be addressed. E-mail: shakhnovich{at}chemistry.harvard.edu
Author contributions: E.J.D. and E.I.S. designed research; E.J.D. and O.A. performed research; J.G. contributed new reagents/analytic tools; E.J.D., O.A., and E.I.S. analyzed data; and E.J.D. and E.I.S. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0702766104/DC1.
Abbreviations:

PPI,

protein–protein interaction;

Y2H,

yeast two-hybrid;

MCID,

Monte Carlo interaction diffusion.