Atomic structure, interactions and dynamics are core to understanding bio-molecular mechanism. The Chapman group uses an array of physical and biological experiments to build and refine computational models of molecular structure-dynamics that explain function.
Using X-ray crystallography, we have determined the atomic structure of adeno-associated virus (AAV), a leading DNA-delivery vector for treating genetic diseases by gene therapy. We have recently screened the human genome for genes essential to AAV's cellular entry, identifying a recycling receptor in host cells that is needed for productive viral entry and trafficking towards the nucleus. Electron microscopy is now at the center of efforts to map, in atomic details, the interactions of host proteins with AAV as it enters the cell, preparing a foundation for modulating the specificity of the virus.
Protein motions are often overlooked, because they are difficult to characterize, but they are often critical to function. The rate-limiting millisecond dynamics of arginine kinase provide a window through which we are learning general principles. NMR measurements of local exchange rates are combined with crystallographic structure to model the mechanics of protein dynamics through the reaction cycle of an enzyme. It is providing the first experimental evidence in support of theories predicting heightened, rather than lessened protein dynamics in the transition state. We are now characterizing their nature and relation to intrinsic modes of motion that have evolved in enzymes.
Areas of interest
- Viral-host interactions. Enzyme dynamics. Biophysics. Structural Biology.
- B.S., University of London, Kings College 1982
- M.A.Sc., University of London, Birkbeck College 1983
- Ph.D., University of California, Los Angeles, Los Angeles California 1987
- Fellow, American Association for the Advancement of Science
Memberships and associations
- Knight Cancer Institute Member
- American Crystallography Association
- American Society for Gene & Cell Therapy
- American Society for Virology
- Protein Society