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Nanoseconds molecular dynamics simulation of primary mechanical energy transfer steps in F1-ATP synthase

Abstract

The mitochondrial membrane protein FoF1-ATP synthase synthesizes adenosine triphosphate (ATP), the universal currency of energy in the cell. This process involves mechanochemical energy transfer from a rotating asymmetric γ-'stalk' to the three active sites of the F1 unit, which drives the bound ATP out of the binding pocket. Here, the primary structural changes associated with this energy transfer in F1-ATP synthase were studied with multi-nanosecond molecular dynamics simulations. By forced rotation of the γ-stalk that mimics the effect of proton motive Fo-rotation during ATP synthesis, a time-resolved atomic model for the structural changes in the F1 part in terms of propagating conformational motions is obtained. For these, different time scales are found, which allows the separation of nanosecond from microsecond conformational motions. In the simulations, rotation of the γ-stalk lowers the ATP affinity of the βTP binding pocket and triggers fast, spontaneous closure of the empty βE subunit. The simulations explain several mutation studies and the reduced hydrolysis rate of γ-depleted F1-ATPase.

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Acknowledgements

We thank W. Junge, A. Engel, B. de Groot, B. Heymann, K. Schulten, W. Allison, D. Chandler, V. Helms, M. Hofmann, K. Kinosita, V. Knecht, R. Lang, G. Oster, G. Schröder and H. Wang for stimulating discussions and for critical reading of the manuscript; B. de Groot for help with the GROMACS program package; and G. Schneider and O. Haan for their support. Computer time was provided by the Göttingen computer center (GWDG) and the Paderborn center for parallel computing (PC2).

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The authors declare no competing financial interests.

Correspondence to Helmut Grubmüller.

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Figure 1: ATP synthase structure, function and simulation setup.
Figure 2: Structural changes of the β-subunits induced by enforced rotation of the γ-stalk.
Figure 3: Changes at the catalytic α–β interface.
Figure 4: Sequence and timing of conformational changes in βTP.
Figure 5: Changes at the βTP ATP binding site after the 120° rotation and free dynamics.