Protein:protein interactions require multiple contacts that place in apposition active domains of the two protein partners. Such allosteric interactions are exemplified in protein:receptor interactions, antigen:antibody interactions and alignment of active sites with substrate domains. Considerable conformational flexibility is required in both macromolecular partners to achieve precise alignment.
In earlier studies we examined molecular mechanisms involved in the interactions of the fibrous protein collagen 1, whose functional form is the solid state as bundles of fibers. Most static cells in the body are suspended in a large mass of collagenous matrix to which they are bound firmly through specific receptors, the alpha-2beta1 integrins. This contact not only allows cells to adhere to and migrate on collagen, but the junction between collagen and integrins coupled with a complex of proteins to the cytoskeleton serves as the engine for transduction of force stimuli whose bi-directional flow through this assembly is key to tissue homeostasis, growth, morphogenesis, and remodeling. While most studies describe collagen conformation as rigid, such inflexibility would preclude the kind of transient allosteric interactions necessary for productive cell:collagen contact. We used peptide models and computational techniques to identify domains on collagen molecules on the surface of fibers that would assume at least two iso-energic conformations. A synthetic peptide named P-15 encompassing the cell binding domain GTPGPQGIAGQRGVV has served as a valuable molecular decoy for collagen. Substrates containing this peptide allow cells to adhere, migrate, differentiate, organize 3-D colonies and facilitate in vitro and in vivo tissue engineering. P-15 collagen decoy has been in commerce for over two decades.
Extending this concept to non-fibrous proteins, we have identified sequences in a variety of enzymes that modify other proteins to act as allosteric modulators. Specifically, we have developed molecular decoys that form stable complexes with certain protein kinases, interfering with signaling pathways such as those involving TNF-alpha and NF-kappaB. These molecular decoys inhibit the activation of NF-kappaB, facilitate scar-less repair by attenuating inflammation and fibrosis, and they show remarkable anti-tumor activity in vivo.