Synthetic ATPase

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Background

  • ATP runs reversibly at almost 100% efficiency
    • It can synthesize or hydrolyze ATP
  • The Rotary mechanism exhibits homology with flagellar motors and proton pumps
  • It is the smallest known nanomotor and can be described in terms of its macroscopic structure and mechanics as well as on the atomic and molecular scale


Ideas

  • Can we modify it to generate efficient synthetic nanomotors and circuits?
    • Actuators, hydrogen sensing, energy storage
  • Exploit Modular Nature and develop small-molecule signals to isolate and examine the individual components.
    • Alter or expand the environmental specifications for proper function
    • Change sensitivity to certain signals
  • Develop or discover ligands that modulate ATPase activity
    • Synthetic organic or inorganic molecules
    • Discovery of Natural ligands
    • Directed evolution of natural ligands
    • Single molecule regulation
      • Competitive or noncompetitive effectors
      • Delivering signals: pulse generation, time and frequency dependence
  • Incorporating ATPase or other rotary motors into synthetic systems
    • to produce signals or regulate environmental conditions
    • Control pH by expression/activation of certain genes encoding various subunits
      • In Programmed Bacterial Systems (ex. raising pH increases AHL degradation rate)
      • Hydrogels,Mechanotransduction,Controlling intermolecular forces in the matrix through ionic transport
    • Aptamer-binding targets


Scientific/Engineering Questions

  • Does the number of c subunits in the F0 domain of ATP Syntase correlate to the activity of ATPases?
    • How mutations in c protein expression alter the behavior of the motor? (qualitative/quantitative?)
    • What are other possible targets for site directed mutagenesis?
  • Does expression of certain structures or certain numbers of some subunits correlate with the enzyme's ability to operate in both synthesis and as a proton pump?
  • Can we induce oscillatory or time-delayed responses?
    • Can we discover any natural functions for this such as a role in signaling or regulation?
    • Generate frequency mediated potential differences in cells?
  • Can we use natural or modified structures to examine the role in diseases:
    • ATP synthase defects associated with neuropathy, ataxia and retinitis pigmentosa, Leigh Syndrome, Cancer
    • ATPase as a drug target


Papers

(1) Liu, H.; Schmidt, J. J.; Bachand, G. D.; Rizk, S. S.; Looger, L. L.; Hellinga, H. W.; Montemagno, C. D. Control of a biomolecular motor-powered nanodevice with an engineered chemical switch. Nat. Mater. 2002, 1, 173-177.

(2) Muench, S. P.; Trinick, J.; Harrison, M. A. Structural divergence of the rotary ATPases Q. Rev. Biophys. 2011, 1-46.

(3) Nakamoto, R. K.; Baylis Scanlon, J. A.; Al-Shawi, M. K. The rotary mechanism of the ATP synthase Arch. Biochem. Biophys. 2008, 476, 43-50.

(4) Oster, G.; Wang, H. Reverse engineering a protein: the mechanochemistry of ATP synthase. Biochim. Biophys. Acta 2000, 1458, 482-510.

(5) Simmons, C. R.; Stomel, J. M.; McConnell, M. D.; Smith, D. A.; Watkins, J. L.; Allen, J. P.; Chaput, J. C. A synthetic protein selected for ligand binding affinity mediates ATP hydrolysis. ACS Chem. Biol. 2009, 4, 649-658.

(6) Soong, R. K.; Bachand, G. D.; Neves, H. P.; Olkhovets, A. G.; Craighead, H. G.; Montemagno, C. D. Powering an inorganic nanodevice with a biomolecular motor. Science 2000, 290, 1555-1558.