Welcome to Cheng Lab

Our research aims to understand the structure and function of macromolecular interactions by selected model macromolecular systems. Viral structural proteins have the capacity to function both in assembly and in disassembly, which is made possible through a built-in flexibility triggered by cellular events. We observe conformational changes of viral particles at various states of their life cycle to analyze their assembly intermediates as well as the mature forms. Similarly, infectious virions can be treated with numerous conditions, e.g. receptor-mediated genome release or acid-activated membrane fusion, to observe the key steps of viral re-entry into host cells. Using electron microscopy, we apply a rapid-frozen and low-dose imaging procedure to best preserve the biological specimen in its native form. Computer image processing is developed to retrieve most of the useful signal from the low-contrast micrographs. Technical implementation of cryo-EM, cellular tomography, and computational modeling schemes also enables us to address interactions involved in complex biological molecules and/or nanoscale machines.

Virus assembly: Alphavirus represents one of the best known model systems among enveloped viruses. The RNA genome (red) is packaged into a nucleocapsid (orange for the capsid proteins), which is surrounded by a lipid bilayer (green) with transmembrane spike proteins (blue). One of the questions for this group to investigate is how the viral proteins drive the assembly reactions through the cytoplasm (left), and how the nucleocapsids bud out of the host cell to become a mature virion capable of further infections.

Viral infections require the virus to enter a new cell, multiply, and then to be released to infect further cells. These processes often involve changes in the structures of the viral proteins, and our goal is to determine their conformations at the various stages of an infection. Our research helps not only to explain how the virus functions, but also to design anti-viral drugs more effectively.

The central theme of our research is to understand the structure and function of macromolecular interactions relevant to viral therapy vector design. A fascinating property of viruses is that their structural proteins have the capacity to function both in assembly and in disassembly. This paradox is made possible through a builtin flexibility among many viral proteins, in which an external or internal cellular event may trigger conformational changes. Therefore, we observe virus particles at various states of their life cycle to analyse either their assembly-intermediates or mature forms. Similarly, virus particles can be treated with numerous conditions, e.g. low pH mediated membrane fusion, to observe the key steps of viral attachment and entry into the host cell.

Another extended effort of our research is the continuing development of integrated methods to compute three-dimensional reconstructions. Accurate interpretation based on schemes of exprimental bioinformatics are implemented to better understand the organisation and interactions amongst the viral components. Using electron microscopy, we apply a rapid-frozen and low-dose imaging procedure to best preserve the biological specimen in its native form. Computer image processing is developed to retrieve most of the useful signal from the low-contrast micrographs. Having obtained high resolution structures, the mechanism of virus-host interactions is then investigated by using the structural information to design specific biochemical and genetic experiments and to test the importance of particular residues in the proteins. The atomic models of viral components, such as capsid proteins, is similarly used to determine their individual roles in the processes of host recognition, attachment and penetration to the cell membrane, as well as viral budding and release from the cytoplasm.

Consequently, the improvement of molecular imaging, digital data processing, and advanced computing would provide better tools for observing the dynamic event and various forms of biological molecules in the virus life cycle. One of our goals is to apply the knowledge gained from the viral structures to more effective drug or vaccine design against viral infection. Structural information also faciliates the biomedical research in the design of gene therapy vectors involving virus macromolecules.