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Journal of Chemical Physics / Volume 133 / Issue 20 / ARTICLES / Biological Molecules, Biopolymers, and Biological Systems

J. Chem. Phys. 133, 205101 (2010); http://dx.doi.org/10.1063/1.3516589 (7 pages)

Macromolecular crowding effects on protein–protein binding affinity and specificity

Young C. Kim1, Robert B. Best2, and Jeetain Mittal3

1Center for Computational Materials Science, Naval Research Laboratory, Washington, DC 20375, USA
2Department of Chemistry, University of Cambridge, Cambridge, United Kingdom
3Department of Chemical Engineering, Lehigh University, Bethlehem, Pennsylvania 18015, USA

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(Received 22 July 2010; accepted 26 October 2010; published online 22 November 2010)

Macromolecular crowding in cells is recognized to have a significant impact on biological function, yet quantitative models for its effects are relatively undeveloped. The influence of crowding on protein–protein interactions is of particular interest, since these mediate many processes in the cell, including the self-assembly of larger complexes, recognition, and signaling. We use a residue-level coarse-grained model to investigate the effects of macromolecular crowding on the assembly of protein–protein complexes. Interactions between the proteins are treated using a fully transferable energy function, and interactions of protein residues with the spherical crowders are repulsive. We show that the binding free energy for two protein complexes, ubiquitin/UIM1 and cytochrome c/cytochrome c peroxidase, decreases modestly as the concentration of crowding agents increases. To obtain a quantitative description of the stabilizing effect, we map the aspherical individual proteins and protein complexes onto spheres whose radii are calculated from the crowder-excluded protein volumes. With this correspondence, we find that the change in the binding free energy due to crowding can be quantitatively described by the scaled particle theory model without any fitting parameters. The effects of a mixture of different-size crowders—as would be found in a real cell—are predicted by the same model with an additivity ansatz. We also obtain the remarkable result that crowding increases the fraction of specific complexes at the expense of nonspecific transient encounter complexes in a crowded environment. This result, due to the greater excluded volume of the nonspecific complexes, demonstrates that macromolecular crowding can have subtle functional effects beyond the relative stability of bound and unbound complexes.

© 2010 American Institute of Physics

Article Outline

  1. INTRODUCTION
  2. MODEL AND METHODS
    1. Coarse-grained protein–protein interactions
    2. Coarse-grained representation of crowding agents
    3. Simulation method
    4. Calculation of binding free energy
    5. Structural analysis
  3. RESULTS
  4. CONCLUSIONS

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KEYWORDS and PACS

Keywords

biochemistry, cellular biophysics, macromolecules, molecular biophysics, proteins

PACS

ARTICLE DATA

Digital Object Identifier
http://dx.doi.org/10.1063/1.3516589

PUBLICATION DATA

ISSN

0021-9606 (print)  
1089-7690 (online)

Publisher

$abstract.society.value is a Member of CrossRef American Institute of Physics

For access to fully linked references, you need to log in.
    S. Qin and H. X. Zhou, Phys. Rev. E 81, 031919 (2010).


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