Hsc70 ATPase: an insight into water dissociation and joint catalytic role of K+ and Mg2+ metal cations in the hydrolysis reaction.
Hybrid quantum mechanics/molecular mechanics simulations, coupled to the recently introduced metadynamics method, performed on the adenosine triphosphate (ATP) of the bovine Hsc70 ATPase protein, show which specific water molecule of the solvation shell of the Mg2+ metal cation acts as a trigger in the initial phase of the ATP hydrolysis reaction in ATP synthase. Furthermore, we provide a detailed picture of the reaction mechanism, not accessible to experimental probes, that allows us to address two important issues not yet unraveled: (i) the pathway followed by a proton and a hydroxyl anion, produced upon dissociation of a putative catalytic H2O molecule, that is crucial in the selection of the reaction channel leading to the hydrolysis; (ii) the unique and cooperative role of K+ and Mg2+ metal ions in the reaction, acting as co-catalysts and promoting the release of the inorganic phosphate via an exchange of the OH- hydroxyl anion between their respective solvation shells. This is deeply different from the proton wire mechanism evidenced, for instance, in actin and lowers significantly the free energy barrier of the reaction.
Boero
Mauro
M
Center for Computational Sciences, University of Tsukuba, Tennodai 1-1-1, Tsukuba, Ibaraki 305-8577, Japan. boero@comas.frsc.tsukuba.ac.jp
Ikeda
Takashi
T
Ito
Etsuro
E
Terakura
Kiyoyuki
K
D000251:Adenosine Triphosphatases / Q000737:chemistry*; D002384:Catalysis; D002412:Cations / Q000737:chemistry; D050883:HSC70 Heat-Shock Proteins / Q000737:chemistry*; D006868:Hydrolysis; D008274:Magnesium / Q000737:chemistry*; D011188:Potassium / Q000737:chemistry*; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D011789:Quantum Theory; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D014867:Water / Q000737:chemistry
D002412:Cations; D050883:HSC70 Heat-Shock Proteins; D014867:Water; D000251:Adenosine Triphosphatases; D008274:Magnesium; D011188:Potassium