Grant: Discovery Grants Program - Individual

Enzymes have revolutionized many industrial processes by enabling the efficient catalysis of complex reactions under mild conditions. Modern industrial enzymes are typically heavily engineered to improve and diversify their properties. Given the staggering number of possible protein sequences, this engineering process is generally guided by known structural and functional information. This information is typically obtained using standard structural biology techniques such as X-ray crystallography and nuclear magnetic resonance spectroscopy. These characterization techniques are however poorly suited to the study of enzymes that interact with solids. As a result, designing and engineering such proteins is difficult despite their incredible potential in both bioremediation efforts to combat environmental pollution and biocatalytic applications in the multitrillion-dollar materials industry. My research program seeks to address this challenge by building an understanding of protein-solid interactions and using this information to create novel biosystems that function in this interface. In the long term, we aim to develop a mechanistic understanding of the thermodynamic and structural elements that enable protein-solid interactions. Achieving this goal, however, begins with the development of tools, techniques, and heuristics enabling the study of these interactions. Over the next 5 years, we will address the challenge of studying the protein-solid interactome using an iterative learning platform centered around plastic degrading enzymes (PDEs). We will: �Improve the catalytic efficiency of polyethylene terephthalate (PET)-degrading enzymes by fusion to engineered plastic-binding domains �Identify the sequence and structure motifs of plastic-binding proteins that enable binding to plastics �Characterize the structural dynamics and reaction properties of a family of PDEs and contrast these properties to those of related non-PDEs to build empirical models rationalizing PDE catalytic activity The characterization techniques that we develop and interaction modes that we uncover during these projects will in turn inform our future work. This cycle of designing, building, and testing novel enzymes, and learning from their mechanisms will allow us to progressively deepen our understanding of these difficult-to-study systems and interactions. Ultimately, it will enable the design of complex biocatalysts with tangible industrial and environmental applications. This effort requires multidisciplinary expertise in synthetic and molecular biology, biophysics, materials science, and computation, thereby providing a deep and valuable skill set for the HQP that will contribute to this program over the next 5 years. These trainees, which will include 3 PhD and 2 MSc students, will be the foundation of a new, open-minded research group tackling frontier problems in protein science and biocatalysis.