This Article Full Text Full Text (PDF) Supplement All Versions of this Article: biophysj.106.091108v1 91/9/3436    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Paramore, S. Articles by Voth, G. A. Search for Related Content PubMed PubMed Citation Articles by Paramore, S. Articles by Voth, G. A.

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

Center for Biophysical Modeling and Simulation, and Department of Chemistry, University of Utah, Salt Lake City, Utah 84112-0850

Correspondence: Address reprint requests to Gregory A. Voth, Center for Biophysical Modeling and Simulation, and Dept. of Chemistry, University of Utah, 315 S. 1400 E. Rm 2020, Salt Lake City, UT 84112-0850. E-mail: voth{at}chem.utah.edu.

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. Although 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 -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 -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 -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 after 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 simulation timescales and those of experiment or physiological conditions is also discussed.

This article has been cited by other articles:

				M. Sotomayor and K. Schulten The Allosteric Role of the Ca2+ Switch in Adhesion and Elasticity of C-Cadherin Biophys. J., June 15, 2008; 94(12): 4621 - 4633. [Abstract] [Full Text] [PDF]

				Q. Zhu and R. J. Asaro Spectrin Folding versus Unfolding Reactions and RBC Membrane Stiffness Biophys. J., April 1, 2008; 94(7): 2529 - 2545. [Abstract] [Full Text] [PDF]

				D. T. Mirijanian and G. A. Voth Unique elastic properties of the spectrin tetramer as revealed by multiscale coarse-grained modeling PNAS, January 29, 2008; 105(4): 1204 - 1208. [Abstract] [Full Text] [PDF]