Protein folding, function and engineering

蛋白质是生命的分子机器，执行着广泛的功能，从催化剂到特异性识别和结合其他分子，再到结构支持角色。蛋白质中氨基酸的顺序，即其一级序列，编码蛋白质如何折叠成其功能性“天然”结构。 尽管进行了广泛的研究，但一级序列决定蛋白质折叠和功能的机制仍不清楚。 理解这些机制非常重要，因为最终，这样的理解将使我们能够合理地预测任何蛋白质的行为（例如导致疾病的功能失调的突变蛋白质）。 它还将使我们有能力为生物技术或医学中的任何所需应用工程或设计蛋白质。 最近在蛋白质序列和蛋白质建模方面的巨大进展为理解序列如何决定折叠和功能方面的巨大进展奠定了基础。 例如，我们使用序列信息和建模成功地设计了第一个完全3倍对称的球状蛋白，称为ThreeFoil，它非常稳定，具有糖结合功能。由于许多蛋白质工程尝试失败了，有时是以微妙的方式，我们现在需要进一步分析ThreeFoil，以充分了解我们工程的结果。 我们还建议将我们对ThreeFoil的研究扩展到相关蛋白质，包括其他类型的天然和设计的对称蛋白质。 其中之一，称为Hisactophilin，在控制细胞运动中发挥核心作用，通过其可逆结合细胞膜和其他细胞骨架蛋白，以响应细胞环境产生的pH信号。 我们正在使用Hisactophilin作为模型来理解信号传导和蛋白质的调节，可逆结合。 我们还在研究超声波对这些和其他蛋白质的破坏作用，这对于超声波在工业和医疗应用中的许多应用都很重要。总之，我们的深入研究将导致关于蛋白质如何工作以及如何控制它们的重要新知识。

Proteins are the molecular machines of life, performing a huge range of functions, from acting as catalysts, to specifically recognizing and binding other molecules, to structural support roles. The order of amino acids in a protein, i.e. its primary sequence, encodes how the protein folds into its functional "native" structure. Despite extensive study, the mechanisms by which primary sequence determines protein folding and function remain unclear. Understanding these mechanisms is of tremendous importance because, ultimately, such an understanding will give us the ability to rationally predict the behaviour of any protein (such as a misfunctional mutant protein that causes disease). It will also give us the ability to engineer or design proteins for any desired application in biotechnology or medicine. Tremendous recent advances in knowledge of protein sequences and in protein modeling have set the stage for making dramatic advances in understanding how sequence determines folding and function. For example, we used sequence information and modeling successfully to engineer the first completely 3-fold symmetric globular protein, called ThreeFoil, which is extremely stable and has sugar binding functionality. Since many protein engineering attempts fail, sometimes in subtle ways, we now need to analyze ThreeFoil further to fully understand the outcome of our engineering. We also propose to extend our studies on ThreeFoil to related proteins, including other types of natural and designed symmetric proteins. One of these, called Hisactophilin, plays a central role in controlling the movement of cells by its reversible binding to cell membranes and other cytoskeletal proteins in response to pH signals generated by the cell's environment. We are using Hisactophilin as a model to understanding signaling and regulated, reversible binding by proteins. We are also studying the damaging effects of ultrasound on these and other proteins, which is important for many applications of ultrasound for industrial and medical applications. Together, our in depth studies will lead to important new knowledge on how proteins work and how they can be controlled.