THE STRUCTURES OF LARGE BIOMOLECULES AND BIOMOLECULAR SYSTEMS

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MBRS students working in my laboratory will have the opportunity to work on one or more of several projects that investigate structures of biomolecules and biological systems. They will learn and independently implement essential techniques used in biomedical and biotechnological research. Depending on the students' previous experiences and interests, they may be actively involved in protein purification, isoelectric focussing, qualitative and preparative polyacrylamide gel electrophoresis, ion exchange chromatography and size exclusion chromatography. Specific projects may involve protein crystallization experiments, single-crystal x-ray diffraction experiments, computational approaches such as molecular replacement methods and molecular modeling, preparation of protein/lipid monolayer systems for viewing under an electron microscope, operation of an electron microscope, preparation of liposomes and x-ray scattering experiments on liposomes. Using x-ray diffraction, electron microscopic methods and computational approaches, we are conducting structural studies on diphtheria toxin fragments A and B, and Clostridium difficile toxin A. From our studies we hope to better understand how high molecular weight, hydrophilic molecules such as bacterial protein toxins are capable of translocation across cellular membranes and effecting their cellular targets. Structural information about bacterial protein toxins may also aid in the design of immunotoxins, molecules efficient in killing specific cells in cancer and related diseases. As part of an integrated study of liposomal-based drug delivery systems, we are using x-ray scattering methods to investigate the structural properties of AmBisome, produced by Vestar, Inc. AmBisome is used to treat systemic fungal infections brought on by immune suppression during the onset of AIDS or after organ transplant surgery. The goal of this research is to elucidate liposome structural properties and the inter-molecular interactions of therapeutic agents with the lipid bilayer. This will help us to better understand liposome uptake, processing and reactivity, and allow for future rational design of optimal drug delivery systems to fight cancer and related diseases.