Domain swapping is a consequence of minimal frustration

^*Center for Theoretical Biological Physics and Departments of ^†Physics and ^§Chemistry and Biochemistry, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093

Edited by Harry B. Gray, California Institute of Technology, Pasadena, CA, and approved August 4, 2004 (received for review May 25, 2004)

Abstract

The same energy landscape principles associated with the folding of proteins into their monomeric conformations should also describe how these proteins oligomerize into domain-swapped conformations. We tested this hypothesis by using a simplified model for the epidermal growth factor receptor pathway substrate 8 src homology 3 domain protein, both of whose monomeric and domain-swapped structures have been solved. The model, which we call the symmetrized Gō-type model, incorporates only information regarding the monomeric conformation in an energy function for the dimer to predict the domain-swapped conformation. A striking preference for the correct domain-swapped structure was observed, indicating that overall monomer topology is a main determinant of the structure of domain-swapped dimers. Furthermore, we explore the free energy surface for domain swapping by using our model to characterize the mechanism of oligomerization.

Footnotes

↵ ∥ To whom correspondence should be addressed. E-mail: jonuchic{at}ucsd.edu.
↵ ‡ S.Y. and S.S.C. contributed equally to this work.
↵ ¶ Present address: Institute of Physical Science and Technology, University of Maryland, College Park, MD 20742.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations: SH3, src homology 3; MSH3, monomeric SH3; DSH3, dimeric SH3; Eps8, epidermal growth factor receptor pathway substrate 8.