Program Manager: Dr. Jon Mogford
 Biological systems are based on proteins that are synthesized from a library of 20 naturally occurring amino acids. Nature uses these proteins for signaling, the construction of physical structures, and the control of activities within a cell. Small proteins are composed of approximately 300 amino acids, and hence the sequence, and possibly the structure space, of naturally occurring proteins are vast. The goal of this effort is to create a set of design and synthesis processes that will enable the specification of a desired function, and be able to rapidly synthesize a protein that performs the function. To achieve this goal, significant advances must be made in the understanding of several problems, including the relationship of sequence to physical structure and biological function, and the definition of reusable protein mofifs enabling the equivalent of a periodic table for proteins. Research efforts also involve exploiting the redundancy in amino acid coding and the use of artificial amino acids.
Today what is considered “protein design” is in reality the “redesign” of an existing protein. The Protein Design Processes (PDP) Program changes the paradigm by first understanding of the binding and chemical reaction that is to be expressed; designing an active site that is compatible with the initial, transition, and final state chemistry; and then embedding the resulting structure in a scaffold. To accomplish this goal, DARPA is investing in the development of new tools in diverse areas such as topology, optimization, the calculation of ab initio potentials, synthetic chemistry, and informatics leading to the ability to design proteins to order. At the conclusion of this program, researchers expect to be able to design a new complex protein, within 24 hours, that will inactivate a pathogenic organism.
In the first phase of the program, 10 known enzymatic reactions that span a wide portion of chemical space were chosen as tests for the methodology. Using PDP-developed methods, new enzymes were designed to achieve the 10 specified functions. For all 10 cases, the naturally occurring enzyme was recovered as one of the top 5 designs, validating the PDP methodology. During the second phase of the program, researchers are designing three new enzymes to catalyze reactions with a goal of kcat/kuncat > 105. Preliminary results imply that the program has already achieved one enzyme for which kcat/kuncat > 104 has been achieved.
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