Grant: Discovery Grants Program - Individual

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.