Biochemical, Biophysical and Structural Characterization of Phage Lambda Capsid Assembly and Maturation

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The herpesviruses and many bacteriophages, viruses that infect bacteria, share similar developmental pathways. An essential step for all of them is the assembly of a capsid shell that protects the viral genome in the environment. The capsid self-assembles from multiple copies of a major capsid protein and a scaffolding “chaperone” protein. The interactions required for assembly and subsequent stability of the shell are of fundamental importance to virus replication. This project studies and defines these interactions which will advance our understanding of how the viruses replicate and maintain infectivity in the environment. An understanding of these forces is also necessary for the rational development of anti-viral therapeutics and to adapt the structures for novel nanomaterials for scientific and potentially health-related applications. The work performed in this project will be conducted by promising young scientific investigators from undergraduate to graduate to post-doctoral fellows and will serve to train the next generation of scientists in the American work force.Specifically, the project will define the structural and thermodynamic interactions between the capsid proteins required for shell assembly and stability. The studies will employ biochemical (mutagenesis), biophysical (analytical ultracentrifugation), computational (molecular dynamics) and structural (Nuclear Magnetic Resonance, crystallography, cryo-Electron Microscopy) approaches in a coordinated manner. Fundamental interactions between the scaffolding and capsid proteins required for high-fidelity shell assembly are also interrogated. The results of the studies will reveal molecular interactions essential to shell assembly and stability in the large double-stranded DNA viruses, both prokaryotic and eukaryotic. These data have significant implications in anti-viral therapeutics, phage therapy and nanotechnology applications.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.