MODIFICATION
A -- DEFENSE SCIENCES RESEARCH AND TECHNOLOGY
- Notice Date
- 4/11/2006
- Notice Type
- Modification
- NAICS
- 541710
— Research and Development in the Physical, Engineering, and Life Sciences
- Contracting Office
- Other Defense Agencies, Defense Advanced Research Projects Agency, Contracts Management Office, 3701 North Fairfax Drive, Arlington, VA, 22203-1714
- ZIP Code
- 22203-1714
- Solicitation Number
- BAA06-19
- Response Due
- 2/9/2007
- Archive Date
- 2/9/2007
- Description
- DISREGARD THE INFORMATION POSTED APRIL 11, 2006 FOR MODIFICATION 2 (ADDENDUM 2) to BAA06-19. THE FOLLOWING IS THE CORRECT INFORMATION FOR ADDENDUM 2 to BAA06-19. CONTROL OF PROTEIN CONFORMATION (CPC) SOL BAA 06-19, Addendum 2, DUE: June 29, 2006. TECHNICAL POC: Dr. Donald J. Leo, DARPA/DSO, Ph: (571) 218-4939, Email: baa06-19@darpa.mil; URL: www.darpa.mil/dso. Website Submission: http://www.sainc.com/dso0619/ DESCRIPTION The Defense Advanced Research Projects Agency (DARPA) is seeking innovative proposals for the development of technologies that enable modulation of single protein affinity, activity, and selectivity through real-time control of single protein conformation. Real-time control of protein conformation will enable the development of biosensors with tunable detection characteristics, and improved countermeasures for defense against chemical and biological attack. In addition, the technologies developed under this Program will permit novel studies of the relationship between protein structure and function, thus enabling fundamental discoveries in the biological and medical sciences. Proposals are requested for research programs that demonstrate the ability to modulate single protein affinity, activity, and selectivity through control of single protein conformation. It is expected that each research effort will consist of an interdisciplinary team with expertise in the following technical areas: 1) Techniques for isolating single proteins of interest to chemical and biological defense, and developing assays that accurately measure single protein affinity, activity, and selectivity; 2) Techniques for real-time manipulation of single protein conformations; 3) Computational techniques that support the development of methods for real-time control of single protein conformations. BACKGROUND The inherent relationship between protein structure and function implies that the direct manipulation of a protein?s structure will alter its function. The ability to alter structure/function in a specific way would have application in biosensors that utilize biomolecules (e.g., antibodies) or development of biomolecule-based medical countermeasures (e.g., butyrylcholinesterase). For example, the binding affinities and selectivity of an antibody-based biosensor might be tuned or optimized in real-time to maximize detection of analytes of interest while at the same time reducing false alarms from environmental interferents. Similarly, the functional properties of an enzyme might be manipulated in real-time as part of a method for detection of chemical and biological agents or as part of a new countermeasure for chemical and biological defense. Novel molecular processes such as ?rapid prototyping? of new enzyme structures and functions might also be enabled by the ability to control protein conformations in real-time. It is the goal of this Program to develop the technologies that allow this vision to be realized. While the tertiary structure of a protein might be dictated by the primary amino acid sequence, that structure is readily affected by changes in pH, temperature, applied electric fields, or mechanical forces. Many years of ensemble studies have yielded significant information about the relationship between structure and function, and supported a large number of theoretical and computational methods that explain or rationalize that relationship. Compared to ensemble methods, single molecule measurements will provide superior temporal and spatial resolution, and new insights into the structure/function and protein folding problems. The means for monitoring and altering the conformation of a single protein have only been recently developed. For example, single molecule microscopy now permits the visualization of fluorescent probes that monitor protein structure and conformational changes. Optical or AFM-based methods allow the direct application of forces to single proteins as they fold. If real-time manipulation of protein structure/function is to be realized, these single molecule methods must be combined to achieve significant improvements in spatial and temporal resolution, supported by a computational framework that relates conformation to function. Additional innovation is required before a protein?s structure can be continuously ?tuned? in real-time to achieve a desired function. PROGRAM GOALS AND MILESTONES The goal of this Program is to develop tools that enable real-time control and manipulation of single protein conformations so that the functional characteristics of the protein might be tuned or optimized for specific purposes. The CPC Program will be separated into two phases. The goal of Phase I is to demonstrate the ability to modulate the functional characteristics of a single protein through controlled changes in single protein conformation. Depending on the successful Phase I demonstrations, the goal of Phase II will be to demonstrate that real-time control of protein conformation can be incorporated into novel detection methodologies or the development of new medical countermeasures. Phase I will be a research effort of not more than twelve months. Proposals for longer than twelve months will be accepted but only with appropriate justification. The Phase I milestones are: 1) Demonstrate a 10:1 variation in single protein affinity through real-time control of single protein conformation. 2) Demonstrate a 10:1 variation in the relative affinities (i.e., selectivity) for a group of five representative molecules that bind to the protein. 3) Demonstrate a 10:1 variation in single protein activity through real-time control of single protein conformation. This milestone may not be relevant for certain types of proteins under investigation, e.g., antibodies which do not exhibit catalytic activity. Phase II is expected to be a research effort of between twelve and eighteen months. The Phase II milestones will be determined by the results of the Phase I effort and the specific device application that is proposed. To realize the program vision and meet the Phase I milestones, each research effort requires performers with expertise in all of the following areas: 1) Techniques for isolating single proteins of interest to chemical and biological defense, and developing assays that accurately measure single protein affinity, activity, and selectivity Experimental techniques for isolating single proteins for the purpose of characterizing their structure and function are required. Examples include tethering of molecules to substrates, or the use of optical and electrical traps to immobilize single protein macromolecules. Progress in the program will be assessed by measuring the affinity, activity, and selectivity of single proteins, therefore methods for single protein measurements must be clearly defined. Ensemble methods are not deemed to be useful for this program. We are specifically interested in controlling single proteins that enable new advances in the detection of chemical and biological agents, or the development of new countermeasures for chemical and biological attack. 2) Development of techniques for real-time manipulation of protein conformations Techniques for manipulating the conformations of single proteins are required. These include, but are not limited to, the application of mechanical, optical, and electrical stimuli to the single protein for the purpose of changing conformational state. Alteration of the thermal and chemical environment to effect conformation change is potentially of interest (e.g., temperature change, pH change) but is not viewed as a practical method of implementing real-time control. Relevant engineering parameters, such as speed of response, spatial resolution, and repeatability must be defined. In addition to techniques for manipulating conformational changes in proteins, techniques for directly measuring the conformational state of a single protein are required to implement control. These include, but are not limited to, fluorescent techniques and FRET-based techniques that enable real-time measurement of proximity between probes bound to a protein. Novel methods of imaging that have the potential for improved spatial and temporal resolution are also of interest. Concepts for novel hardware, such as advanced detectors and CCD arrays, and novel signal processing methods for real-time measurement, are also of interest if they clearly define how they will improve the state of the art in single protein measurements. Technical details associated with these techniques, such as spatial resolution, temporal resolution, repeatability, and measurement record length, must be defined. Indirect methods of measuring protein conformation, such as the measurement of ionic currents with a patch clamp, are not viewed as useful for this program unless they are coupled with a single protein measurement. 3) Computational techniques that support the development of methods for real-time control of single protein conformations. Computational approaches for modeling the conformational change in proteins that are relevant to chemical and biological countermeasures are required to correlate measurements with a physical understanding of the processes. These include, but are not limited to, normal mode analyses of protein crystal structure; eigenvalue-eigenvector analyses of protein structure; and methods for predicting the global and local response of a single protein to applied stimuli. Of particular importance are computational approaches that predict the relationship between conformation of a single protein and the protein?s affinity, activity, and selectivity, and computational approaches that can predict the changes in conformational state under the action of external stimuli. Coupling computational models with classical and modern control theory is deemed vital to the development of this program. PROPOSAL SUBMISSION As described in BAA 06-19, proposals shall consist of two volumes: Technical and Cost. Only full proposals are being accepted under this addendum. Follow the general guidelines for full proposal format and content provided at: http://www.darpa.mil/dso/solicitations/solicit.htm. Each technical proposal must have a clearly defined research team and management approach. The research team must incorporate people with expertise in all three research areas listed above, and the proposal must clearly define how the team will work together to achieve the program goals. One of the team members must be designated the Principal Investigator. The Principal Investigator will be responsible for coordinating the team and demonstrating the project milestones. Proposals that address only a subset of the research areas listed above or do not contain a clear indication of the Principal Investigator and Management Approach will not be considered for funding. The technical volume of the research proposal must consist of the following sections: 1) Phase I Technical Approach a. Definition of a method for isolating single proteins and measuring the affinity, selectivity, and, if applicable, the activity. b. Definition of a technique for manipulating and characterizing single protein conformation. c. Computational approach for correlating conformational changes in single proteins with functional properties. 2) Phase I milestones: Define a set of interim milestones. The final milestones must include those defined above for the Phase I program. 3) Research Team: Clearly define the expertise of the individual team members and how their expertise relates to the research areas defined in the technical approach. 4) Management Approach: Define a single Principal Investigator who will coordinate the team and be responsible for demonstrating the project milestones. 5) Phase II Concept: Discuss a concept for utilizing the Phase I results in a device or platform that might be applied to the development of novel detection methodologies or medical countermeasures. A Proposer?s Day Workshop will be held on May 22, 2006 in Arlington, Virginia. This day will provide an opportunity for those interested in proposing to seek clarification on the proposal and partnerships critical to programmatic success. A full Special Announcement SN06-23 detailing meeting purpose, location, registration, and other information can be found at http://www.darpa.mil/baa/#dso. . Proposal Deadline Proposals will be due June 29, 2006 NO LATER THAN 4:00 PM ET. Proposals submitted by fax will not be accepted. Evaluation of Proposals Evaluation of the proposals will be in accordance with BAA06-19. For general administrative questions, please refer to the original FEDBIZOPPS solicitation, BAA06-19, of February 8, 2006. http://www.darpa.mil/dso/solicitations/solicit.htm. Address for Proposal Submission: DARPA/DSO, ATTN: BAA06-19, Addendum 2 3701 North Fairfax Drive Arlington, VA 22203-1714 Web address for Proposal Submission: http://www.sainc.com/dso0619/. General Information In all correspondence, reference BAA06-19, Addendum 2. Technical Point of Contact Donald J. Leo, DARPA/DSO; Phone: (571)218-4939; Email: donald.leo@darpa.mil
- Record
- SN01025969-W 20060413/060411221319 (fbodaily.com)
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