Synthetic ATPase

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.