Sub-nanometer resolution imaging of individual biological molecules by electron cryomicroscopy

Many fundamental problems in biology relate to how proteins interact with DNA and RNA. The difficulty in addressing these questions arises from the limitations of current microscopes and the complex and fragile nature of biomolecules. Recent advancesin electron cryomicroscopy (cryo-EM) imaging technology have improved the quality of biological electron microscopy to the point that near-atomic resolution 3D structures are almost routine.

This project will involve improving the resolving power of the electron microscope to allow direct imaging of individual biomolecules with sufficient resolution to understand how they work. The signal in the micrographs, which is used to determine these structures, has not reached the physical limits imposed by radiation damage and detector quantum efficiency. This is because the individual molecules move during electron irradiation. This movement blurs the images of the molecules, thus reducing the structural information available in each micrograph. We have recently developed new specimen supports that that nearly eliminate substrate motion during irradiation. This increases the sub-nanometer image contrast such that the helices of individual proteins are resolved in single images. The project will extend this work to reengineer how microscopes are designed, constructed and used to image biological molecules. This will enable direct observation of the detailed features of biomolecules as they function.

The ideal candidate will have a strong background in physics or engineering and be interested in applying theses skills to important biological problems. This will involve the development of new instruments and methods to improve our ability to image, proteins, DNA, RNA and their interactions with complex macromolecular machines. A knowledge of optics and experience with electronics and vacuum systems will be particularly useful.