Protein Folding, Function and Engineering

蛋白质是精密的分子机器——它们发挥着广泛的功能，从充当催化剂，到专门识别和结合各种分子，再到结构支持作用。线性蛋白质链中氨基酸的顺序，即一级序列，编码蛋白质如何折叠成其功能性的“天然”结构。尽管进行了广泛的研究，但初级序列决定蛋白质折叠和功能的机制细节仍然不清楚。确定这些机制非常重要，因为最终，这些知识将使我们能够准确预测任何蛋白质在自然过程、疾病和生物技术中的行为。它将使我们能够为任何所需的应用设计或工程蛋白质！

Proteins are exquisite molecular machines-they perform a vast range of functions, from acting as catalysts, to specifically recognizing and binding all kinds of molecules, to structural support roles. The order of amino acids in the linear protein chain, i.e. the primary sequence, encodes how the protein folds into its functional “native” structure. Despite extensive study, the details of the mechanisms by which primary sequence determines protein folding and function remain obscure. Defining these mechanisms is of tremendous importance because, ultimately, such knowledge will give us the ability to accurately predict the behaviour of any protein, in natural processes, in disease, and in biotechnology. It will give us the ability to engineer or design proteins for any desired application! Natural and engineered proteins are widely used in research and industry and are transforming biotechnology through their applications in material science, sensors and as drugs, for example. Explosive growth in knowledge of protein sequences, structures and functions and in computational modeling of proteins have set the stage for elucidating exactly how sequence determines folding and function. For example, we developed and demonstrated a successful sequence bioinformatics and modelling method to engineer a protein (called ThreeFoil) with a desired structure (three-fold symmetric superfold) and function (trivalent carbohydrate binding). We showed ThreeFoil is super stable against harsh conditions, and defined a general mechanism that explains this rare and desirable property for a great many proteins. Our discoveries for ThreeFoil and other proteins (including numerous mutants which we design to systematically advance our knowledge) are obtained using a battery of experimental (spectroscopy, calorimetry, microscopy) and computational methods/tools. Bacteria are commonly used for the large scale production of proteins, which may be correctly folded and soluble, or misfolded into insoluble (but still sometimes functional) aggregated structures called inclusion bodies (IBs). We will extend our initial exciting discoveries of the molecular mechanisms of IB formation, in order to better predict and control their formation and properties. Collectively, our research will advance knowledge of how proteins work and how they can be harnessed for myriad applications; it will provide valuable collaborative interdisciplinary and international training for many highly qualified personnel in developing proteins for further great benefit to society.