Assemblies composed of tens to hundreds of subunits drive many essential processes in biological systems by transducing physicochemical signals from their environment into directed conformational change. As they perform their functions, these assemblies often exhibit significant structural changes with hundreds of subunits moving in concert. Little is understood about how these massive assemblies function in their stochastic microscopic environment, how efficiently conformational transitions are effected, and the extent to which subunits within the assemblies behave cooperatively.

The protective protein capsids of many viruses exhibit some of the most dramatic conformational changes among large macromolecular assemblies. The bacteriophage HK97 head assembly is an excellent model system for studies of viral capsid dynamics. Many aspects of the changes that occur in HK97 are believed to be common to most dsDNA phages as well as herpesviruses. In dsDNA bacteriophages, the capsid assembles first as a complete precursor shell (prohead), then DNA is actively pumped into the shell by an ATP-powered portal-terminase complex. DNA packaging induces the hundreds of capsid subunits to rearrange dramatically, bolstering inter-subunit interactions and expanding the capsid shell. This process is termed maturation.

Solution small-angle X-ray scattering and single-particle fluorescence microscopy are being used to characterize the mechanics that take place during maturation of these complex macromolecular machines.

Based on this knowledge, we are starting to re-engineer the capsid for use as nano-scale protein therapeutic delivery devices.