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Biophys J, March 2001, p. 1151-1168, Vol. 80, No. 3

Molecular Dynamics Study of the Energetic, Mechanistic, and Structural Implications of a Closed Phosphate Tube in ncd

Todd J. Minehardt,* Roger Cooke,dagger Edward Pate,Dagger and Peter A. Kollman*

 *Department of Pharmaceutical Chemistry and  dagger Department of Biochemistry and Biophysics and Cardiovascular Research Institute, University of California, San Francisco, California 94143, and  Dagger Department of Pure and Applied Mathematics, Washington State University, Pullman, Washington 99164 USA

The switch 1 region of myosin forms a lid over the nucleotide phosphates as part of a structure known as the phosphate-tube. The homologous region in kinesin-family motors is more open, not interacting with the nucleotide. We used molecular dynamics (MD) simulations to examine a possible displacement of switch 1 of the microtubule motor, ncd, from the open conformation to the closed conformation seen in myosin. MD simulations were done of both the open and the closed conformations, with either MgADP or MgATP at the active site. All MD structures were stable at 300 K for 500 ps, implying that the open and closed conformers all represented local minima on a global free energy surface. Free energy calculations indicated that the open structure was energetically favored with MgADP at the active site, suggesting why only the open structure has been captured in crystallographic work. With MgATP, the closed and open structures had roughly equal energies. Simulated annealing MD showed the transformation from the closed phosphate-tube ncd structure to an open configuration. The MD simulations also showed that the coordination of switch 1 to the nucleotide dramatically affected the position of both the bound nucleotide and switch 2 and that a closed phosphate-tube may be necessary for catalysis.

Biophys J, March 2001, p. 1151-1168, Vol. 80, No. 3
© 2001 by the Biophysical Society   0006-3495/01/03/1151/18  $2.00


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