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Biophys. J. BioFAST: First Published August 4, 2006. doi:10.1529/biophysj.106.091108
© 2006 by the Biophysical Society.

A more recent version of this article appeared on November 1, 2006.
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PROTEINS

Examining the Influence of Linkers and Tertiary Structure in the Forced Unfolding of Multiple-Repeat Spectrin Molecules

Sterling Paramore 1 and Gregory A. Voth 1*

1 University of Utah

* To whom correspondence should be addressed. E-mail: voth{at}chem.utah.edu.

Submitted on June 11, 2006
Revised on July 12, 2006
Accepted on 25 July 2006


  Abstract
The unfolding pathways of multiple-repeat spectrin molecules were examined using steered molecular dynamics (SMD) simulations to forcibly unfold double- and triple-repeat spectrin molecules. While SMD has previously been used to study other repeating-domain proteins, spectrin offers a unique challenge in that the linker connecting repeat units has a definite secondary structure, that of an {alpha}-helix. Therefore, the boundary conditions imposed on a double- or triple-repeat spectrin must be carefully considered if any relationship to the real system is to be deduced. This was accomplished by imposing additional forces on the system which ensure that the terminal {alpha}-helices behave as if there were no free noncontiguous helical ends. The results of the SMD simulations highlight the importance of the rupture of the {alpha}-helical linker on the subsequent unfolding events. Rupture of the linker propagates unfolding in the adjacent repeat units by destabilizing the tertiary structure, ultimately resulting in complete unfolding of the affected repeat unit. Two dominant classes of unfolding pathways are observed following the initial rupture of a linker which involve either rupture of another linker (possibly adjacent), or rupture of the basic tertiary structure of a repeat unit. The relationship between the force response observed on simulations time-scales and those of experiment or physiological conditions is also discussed.

Key Words: atomic force microscopy, protein unfolding, spectrin, steered molecular dynamics




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Copyright © 2006 by the Biophysical Society.