NASHVILLE, Tenn. – Vanderbilt University researchers, in conjunction with colleagues at several other institutions, are working on a project that promises significant improvement in the control of proteins for a number of uses, including the detection of chemical and biological weapons.

Real-time control of the function of single proteins by detecting and changing their shapes is the object of the new research project, called SPARTAN, which signifies Single Protein Actuation by Real-Time Transduction of Affinity in Nanospace. The project is headed by scientists at the Vanderbilt Institute for Integrative Biosystems Research and Education.

“In the area of chemical and biological agent sensors, the controllable protein is the equivalent of the transistor in microelectronics,” said John Wikswo, the Gordon A. Cain University Professor at Vanderbilt and director of the project.

“The single transistor was a technical breakthrough, but its true potential was not realized until millions of transistors were combined on individual microcircuits,” Wikswo said. “Similarly, the true potential of controllable proteins will be realized when we can combine them into large arrays that can be dynamically tuned to respond to a wide variety of different agents.”

The Defense Advanced Research Projects Agency is funding the first phase of the one-year project with $1.3 million because such a capability would provide the foundation for a new class of advanced sensors for applications, including the detection of chemical and biological weapons.  

The interdisciplinary SPARTAN project brings together researchers from Vanderbilt University, University of Tennessee Space Institute, University of Texas at Austin, University of Wisconsin-Madison, University of Tennessee and Oak Ridge National Laboratory.

Proteins are a natural means to detect chemical and biological agents (CB) because many such agents are themselves proteins or small molecules that bind to proteins. Scientists already have the capability to produce proteins that can bind to, and thereby detect or deactivate, known CB agents. Now the challenge is how to respond to new and unknown agents. That is where controllable proteins come in. They could provide the basis of extremely flexible and responsive sensor systems that can rapidly identify unknown chemical and biological threats. In addition, development of such a system should significantly improve understanding of the relationship between protein structure and function.

While the idea of controlling individual proteins may seem futuristic, most of the underlying tools already exist. For some time, scientists have known that a protein’s shape determines its function. Today, understanding of the relationship between their structure, the way in which they change shape and their biological function is growing dramatically. Combine this with a number of other recent developments – the capability to design and fabricate tailored proteins, the ability to use optical spectroscopy to monitor the shape of individual proteins, plus assorted advances in nanophotonics, biophotonics, micro- and nano-fluidics and modern control theory – and the result could be an important new national resource, according to the proposal.

The project requires the combined expertise of researchers in a number of different fields:

• Vanderbilt University researchers have developed the capability to isolate and manipulate individual proteins within microfluidic and nanofluidic devices and to use nature to sort through billions of different protein possibilities to find those that bind most strongly under given conditions.

• University of Texas at Austin researchers have created highly efficient antibodies to anthrax-related biomolecules that will be used as the target proteins for initial demonstrations, have developed the means to insert organic chemicals in specific locations within proteins and have developed computer models for predicting the properties of such engineered proteins.

• University of Wisconsin-Madison researchers have synthesized a class of organic chemicals that can be specifically attached to proteins and cause them to reversibly change shape when exposed to light of different colors.

• University of Tennessee Space Institute researchers have developed custom single-molecule microscopes with multi-color lasers and advanced control electronics and a laser nano-machining capability that can produce novel nanoscale platforms for the single-protein experiments. Researchers at University of Tennessee have expertise in state-of-the-art control theory.

• Oak Ridge National Laboratory researchers provide expertise and unique facilities for fabrication, characterization and imaging of nanoscale features to be used in the research.

The goal of the first phase of the project is to prove that it is possible to reversibly control the conformation of a single protein in real time. In the second phase the researchers will attempt to incorporate real-time control of protein conformation into novel technologies for the detection of chemical or biological threat agents. Further information can be found at http://www.darpa.mil/dso/thrust/biosci/cpc.htm.