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Originally published as Biophys J. BioFAST on January 20, 2006.
doi:10.1529/biophysj.105.072900
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Biophysical Journal 90:2445-2449 (2006)
© 2006 The Biophysical Society

The Open Nucleotide Pocket of the Profilin/Actin X-Ray Structure Is Unstable and Closes in the Absence of Profilin

T. J. Minehardt *, P. A. Kollman *, R. Cooke {dagger} {ddagger} and E. Pate §

* Department of Pharmaceutical Chemistry and {dagger} Department of Biochemistry and Biophysics, and {ddagger} Cardiovascular Research Institute, University of California, San Francisco, California; and § Department of Mathematics, Washington State University, Pullman, Washington

Correspondence: Address reprint requests to E. Pate, Dept. of Mathematics, Washington State University, Pullman, WA 99164. Tel.: 509-335-3151; Fax: 509-335-1188; E-mail: epate{at}wsu.edu.

The open nucleotide pocket conformation of actin in the profilin:actin•CaATP x-ray structure has been hypothesized to be a crucial intermediate for nucleotide exchange in the actin depolymerization/polymerization cycle. The requirement for ancillary modification of actin for crystallization leads to ambiguities in this interpretation, however. We have used molecular dynamics simulations to model the thermodynamic properties of the actin x-ray structure, outside the crystal lattice, in an aqueous environment with profilin removed. Our simulations show that the open-nucleotide-pocket, profilin-free structure is actually unstable, and closes. The coordination of actin to the nucleotide in the molecular-dynamics-derived closed structure is virtually identical to that in the closed profilin:actin•SrATP x-ray structure. Thus, there is currently no thermodynamically stable structure representing the open-nucleotide-pocket state of actin.




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