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Multi-repeat unfolding in steered molecular dynamics on spectrin family proteins



Multi-repeat unfolding in steered molecular dynamics on spectrin family proteins



Biophysical Journal 86(1): 413a, January



When protein unfolding is mechanically constrained to occur directionally, the definition of a domain can prove subtle. Spectrin repeats invariably consist of 3-helix bundles but also appear linked in series by alpha-helices that extend from one repeat to the next. The recent crystal structures of tandem repeats that show this contiguous helix include structures for alpha-actinin as well as spectrin - proteins that are regularly subject to mechanical stress. Our recent single molecule AFM experiments (Law et al, 2003) indicate that unfolding of tandem repeats can occur almost half the time a chain is pulled upon, suggesting that the contiguous helix between repeats propagates a helix to coil transition. Here we report the results of atomistic steered molecular dynamics (SMD) simulations of tandem repeats of the homologous spectrin repeats 1-2 and 2-3 of alpha-actinin. The system consists of the two repeats in a box of explicit water at a respective temperature and pressure of 300 K and 1.0 atm. The SMD simulation was performed after 1.0 ns of equilibration by extending the molecule between its N and C termini at a constant rate of 5X106 nm/ms. We collected a total of five 1.5 ns-trajectories, each starting with a different initial configuration, on which basis we propose a theory for the role of "inter-repeat" helical linkers in the mechanical properties of linked repeats. Temperature effects and mutations are also being studied in order to obtain a refined picture of the unfolding pathways of cytoskeletal proteins.

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Accession: 035349466

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