Attaching a “molecular spring” (blue) to an enzyme (green), we mechanically deform the enzyme, and control its activity. [Phys. Rev. Lett. 95, 078102 (2005)]

The bar-graph shows that the enzymatic activity is shut off under stress (ds), compared to no stress (ss).

Nana-mechanical protein control - DMR 0405632Giovanni Zocchi, PI (Physics & Astronomy Dept. UCLA)

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This “artificial allostery” enables continuous external control of the enzyme, shown in the graph, where increasing L corresponds to increasing stiffness of the spring.

Through this nanotechnology approach we hope to build devices to control parts ofthe molecular machinery of the cell.

Nana-mechanical protein control - DMR 0405632Giovanni Zocchi, PI (Physics & Astronomy Dept. UCLA

• Proteins are Nature’s answer to the nano-technology challenge. Protein molecules perform all tasks in the living cell, catalyzing metabolic reactions, controlling gene expression, pumping ions in and out of the cell, and more. Perhaps the most essential common design feature of proteins is a property called “allostery”: the ability of a protein molecule to react to a chemical stimulus (the binding of another molecule) through a change in conformation (a change in the three-dimensional shape of the protein) which regulates its function.

• We have devised a unique way to elicit such conformational changes, through mechanical control at the molecular scale. We attach a “molecular spring” to the protein and control the spring’s stiffness externally, forcing the protein to assume this or that conformation. This strategy to create “artificial allostery” is applicable to virtually any protein or protein complex. We can use these new molecules (the protein plus the spring) to study in new ways the natural mechanisms of allostery, and we believe we can use them to make new molecular devices, such as amplified molecular probes and “intelligent” drugs.

• This research effort represents a different approach to protein engineering, based more on nano-technology (viewed as “manipulating matter at the nm scale with the purpose of creating new devices”) rather than traditional molecular biology.

• Research in the PI’s lab is synergistic with the newly established Biophysics Major in the undergraduate curriculum within the Physics Department at UCLA.

• This research cuts across disciplines, broadening the scientific outlook of the graduate students involved, who get trained in the current frontiers of molecular biophysics and nano-technology.

• One graduate student (Brian Choi, now a postdoc at Stanford) obtained these results, and two graduate students are carrying on this project at present.

• This research has been featured on the UCLA website, in physics and nanotechnology news journals and websites (Phys. Rev. Focus, NanoBiotech News, Physorg.com, foresight.org, etc.), on the NSF website and the NSF multimedia gallery “Imagine That !”, and on the 2006 APS calendar.

If it proves possible to use our approach to artificial allostery in vivo, for example by developing “smart” drugs which are active only in certain cells and not others, then this research could ultimately have a large societal impact in terms of therapeutics. At present, we do not know whether such promise will come true.

Broader impact