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Published February 4, 2003 | Supplemental Material + Published
Journal Article Open

The missing link between thermodynamics and structure in F_1-ATPase


F_1F_o-ATP synthase is the enzyme responsible for most of the ATP synthesis in living systems. The catalytic domain F_1 of the F_1F_o complex, F_1-ATPase, has the ability to hydrolyze ATP. A fundamental problem in the development of a detailed mechanism for this enzyme is that it has not been possible to determine experimentally the relation between the ligand binding affinities measured in solution and the different conformations of the catalytic β subunits (β_(TP), β_(DP), β_E) observed in the crystal structures of the mitochondrial enzyme, MF_1. Using free energy difference simulations for the hydrolysis reaction ATP+H_2O → ADP+P_i in the β_(TP) and β_(DP) sites and unisite hydrolysis data, we are able to identify β_(TP) as the "tight" (K_D = 10^(−12) M, MF_1) binding site for ATP and β_(DP) as the "loose" site. An energy decomposition analysis demonstrates how certain residues, some of which have been shown to be important in catalysis, modulate the free energy of the hydrolysis reaction in the β_(TP) and β_(DP) sites, even though their structures are very similar. Combined with the recently published simulations of the rotation cycle of F_1-ATPase, the present results make possible a consistent description of the binding change mechanism of F_1-ATPase at an atomic level of detail.

Additional Information

© 2003 National Academy of Sciences. Contributed by M. Karplus, December 6, 2002. Published ahead of print January 27, 2003. We thank A. Dinner and A. E. Senior for reading the manuscript and making many useful suggestions. We thank J. E. Walker and A. G. W. Leslie for providing some of the structures used in the simulations before publication. We thank I. Andricioaei, R. Bitetti-Putzer, P. Maragakis, and R. Petrella for advice concerning the calculations. We thank R. Yelle for his assistance with the local computing environment. Some of the computations were done at the National Energy Research Scientific Computing Center. The research was supported in part by a grant from the National Institutes of Health.

Attached Files

Published - PNAS-2003-Yang-874-9.pdf

Supplemental Material - 7432Fig5.pdf

Supplemental Material - 7432Fig6.pdf

Supplemental Material - 7432Fig7.pdf


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