Proteins are the working horse of the cellular machinery. They are responsible for diverse functions ranging from molecular motors to signaling. Maybe the most common dominator of all proteins is their ability to interact with one another, and with many other types of molecules, whether small or large. Not only do proteins interact with most known chemical components, they do so specifically. In other words, they interact at a specific location, with a specified affinity and kinetics. One of the most exiting fronts in computational protein-protein interactions is the use of the existing knowledge on protein-protein interactions for interface design. Design can be aimed in increasing the affinity of a complex or changing its binding specificity. Here, I will present three methods of protein-design. The first method utilizes the algorithm PARE, developed in my lab to specifically enhance the rate of association and by this the affinity of the protein-complex. The success of the method is demonstrated on the protein pairs TEM-BLIP and Ras-Ral. The second design method comes to change the binding specificity between a pair of proteins, while maintaining the high affinity. To be able to do this successfully we took advantage of the modular architecture of protein-interfaces, and devised a method to alter specifically one module. This was done by seeking in the PDB a similar module (in structure) but not in sequence. This module was incorporated into the interface of TEM1-BLIP replacing the original one. This resulted in a TEM1-BLIP interface with new specificity. In a third project I will demonstrate how engineering Interferon for high binding affinity to its receptors altered its biological activity in a differential manner, demonstrating the use of protein-engineering to make more potent therapeutic proteins.

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