Investigating symmetry-breaking events in living cells and controlling properties of materials using dynamic peptide-based ligands

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Controlling the function of bioactive molecules in specific locations (e.g. drugs in specific parts of the body) can change our approach to human health and drug discovery. Ability to control the properties of materials remotely can open a new era in the engineering of biomaterials. This proposal describes peptide ligands that control the spatial and temporal functions of molecules in living organisms and properties of materials. Living organisms use a universal mechanism for organizing the molecules in space and time. Molecules in cells interact with one another through molecular recognition; turning this recognition process "on" and "off" in each molecule is the basis of all mechanisms of cell function. In our research program, we will identify molecules with similar dynamic properties. Their function will switch "on" and "off" in response to visible light. To generate these molecules, we will start from viruses (phages) that display short peptides on their surface, and modify them with azobenzene (a molecule sensitive to light). We will use >10^9 of different phages to display billions of light-sensitive peptides; each phage can be easily identified using its DNA. Using this technology, it is simple to find molecules that have a specific function, which can be switched "on" or "off" in response to light. In one application, we will find peptides that can regulate distribution of molecules inside the livings cells and regulate asymmetric cell division-a process that occurs in every stem cell in our body. These findings can lead to the development of drugs that control growth of healthy tissues and tumors. In the second project, we will control the distribution of molecules inside multi-cellular tissues using materials that can selectively block the diffusion of specific biomolecules (e.g. protein growth factors). These materials will be based on a dense display of peptides that bind these growth factors. Finally, lessons from organisms that use peptides to accelerate the freezing of water inspired a strategy for dynamic control of properties of materials. From the collection of light-sensitive peptides, we will select those that accelerate the freezing of water in response to light. A similar approach might enable the control of properties of materials using light.