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ATP Hydrolysis in the ß_TP and ß_DP Catalytic Sites of F₁-ATPase

Markus Dittrich ^* , Shigehiko Hayashi   and Klaus Schulten ^* 

^* Beckman Institute, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801; Department of Physics, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801; Theoretical Chemistry Division, Fukui Institute for Fundamental Chemistry, Kyoto University, Kyoto 606-8103, Japan; and Japan Science and Technology Agency, Kawaguchi, Saitama, Japan

Correspondence: Address reprint requests to Klaus Schulten, Beckman Institute, University of Illinois at Urbana-Champaign, 405 N. Mathews Ave., Urbana, IL 61801. Tel.: 217-244-1604; Fax: 217-244-6078; E-mail: kschulte{at}ks.uiuc.edu.

The enzyme F₁-adenosine triphosphatase (ATPase) is a molecular motor that converts the chemical energy stored in the molecule adenosine triphosphate (ATP) into mechanical rotation of its -subunit. During steady-state catalysis, the three catalytic sites of F₁ 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 F₁ 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 ß_TP and ß_DP catalytic sites of F₁-ATPase. Our simulations reveal a dramatic change in the reaction energetics from strongly endothermic in ß_TP to approximately equienergetic in ß_DP. The simulations identify the responsible protein residues, the arginine finger R373 being the most important one. Similar to our earlier study of ß_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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