The Protein Design Processes (PDP) program changes this paradigm by first understanding 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 embedding the resulting structure in a scaffold.
Biological systems are based on proteins synthesized from a library of 20 naturally occurring amino acids. Nature uses these proteins for signaling, construction of physical structures, and control of activities within a cell. Small proteins are composed of approximately 300 amino acids; the sequence and possibly the structure space of naturally occurring proteins are vast. The goal of Protein Design Processes (PDP) program is to create a set of design and synthesis processes that will enable specification of a desired function and be able to rapidly synthesize a protein that performs that 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 motifs enabling the equivalent of a periodic table for proteins. Research efforts also involve exploiting 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 PDP program changes this paradigm by first understanding 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 embedding the resulting structure in a scaffold. DARPA is investing in the development of new tools in diverse areas such as topology, optimization, 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 in 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.