TCB Publications - Abstract

Markus Dittrich, Shigehiko Hayashi, and Klaus Schulten. ATP hydrolysis in the βTP and βDP catalytic sites of F1-ATPase. Biophysical Journal, 87:2954-2967, 2004. (PMC: 1304769)

DITT2004 The enzyme $\mathrm{F_1}$-adenosine triphosphatase (ATPase) is a molecular motor that converts the chemical energy stored in the molecule adenosine tri-phosphate (ATP) into mechanical rotation of its $\gamma$ sub-unit. During steady state catalysis, the three catalytic sites of $\mathrm{F_1}$ operate in a cooperative fashion such that at every instant each site is in a different conformation corresponding to a different stage along the catalytic cycle. Notwithstanding a large amount of biochemical and, recently, structural data we still lack an understanding of how ATP hydrolysis in $\mathrm{F_1}$ is coupled to mechanical motion and how the catalytic sites achieve cooperativity during rotatory catalysis.

In this publication we report combined quantum mechanical/molecular mechanical simulations of ATP hydrolysis in the $\mathrm{\beta_{TP}}$ and $\mathrm{\beta_{DP}}$ catalytic sites of $\mathrm{F_1}$-ATPase. Our simulations reveal a dramatic change in the reaction energetics from strongly endothermic in $\mathrm{\beta_{TP}}$ to approximately equienergetic in $\mathrm{\beta_{DP}}$. The simulations identify the responsible protein residues, the arginine finger $\alpha$R373 being the most important one. Similar to our earlier study of $\mathrm{\beta_{TP}}$, we find a multicenter proton relay mechanism to be the energetically most favorable hydrolysis pathway. The results elucidate how cooperativity between catalytic sites might be achieved by this remarkable molecular motor.

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