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

控制特定位置的生物活性分子的功能(例如，身体特定部位的药物)可以改变我们对人类健康和药物发现的方法。远程控制材料性能的能力可以开启生物材料工程的新纪元。这项建议描述了控制活的生物体中分子的空间和时间功能以及材料性质的多肽配体。 生物有机体使用一种通用的机制来组织空间和时间中的分子。细胞中的分子通过分子识别相互作用；在每个分子中打开和关闭这种识别过程是细胞功能的所有机制的基础。在我们的研究计划中，我们将识别具有相似动力学性质的分子。它们的功能会在可见光的情况下切换“开”和“关”。为了产生这些分子，我们将从表面显示短肽的病毒(噬菌体)开始，并用偶氮苯(一种对光敏感的分子)来修饰它们。我们将使用10^9个不同的噬菌体展示数十亿个光敏肽；每个噬菌体都可以很容易地使用其DNA进行识别。使用这项技术，很容易找到具有特定功能的分子，这些分子可以对光做出反应，打开或关闭。在一个应用中，我们将找到能够调节活细胞内分子分布和调节不对称细胞分裂的多肽--这一过程发生在我们身体的每个干细胞中。这些发现可能导致控制健康组织和肿瘤生长的药物的开发。在第二个项目中，我们将使用可以选择性地阻止特定生物分子(例如蛋白质生长因子)扩散的材料来控制多细胞组织中分子的分布。这些材料将基于结合这些生长因子的多肽的密集展示。最后，从生物利用多肽加速水冻结的经验教训启发了一种动态控制材料特性的策略。从收集的光敏肽中，我们将选择那些加速水冻结对光的响应。一种类似的方法可能使用光控制材料的属性成为可能。

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.