SCIENCE AT THE EDGE SEMINAR

QB/GEDD

Friday, April 11 at 11:30am

Room 1400 Biomedical and Physical Sciences Bldg.

Refreshments at 11:15

Angela Gronenborn

Department of Structural Biology and Pittsburgh Center for HIV-Protein Interaction

University of Pittsburgh School of Medicine, Pittsburgh, PA

Synergy between NMR, cryo-EM and large-scale MD simulations

Novel Findings for HIV Capsid Function

Mature HIV-1 particles contain a conical-shaped capsid that encloses the viral RNA genome and performs essential functions in the virus life cycle. Previous structural analysis of two- and three-dimensional arrays provided a molecular model of the capsid protein (CA) hexamer and revealed three interfaces in the lattice. Using the high-resolution NMR structure of the CA C-terminal domain (CTD) dimer and in particular the unique interface identified, it was possible to reconstruct a model for a tubular assembly of CA protein that fit extremely well into the cryoEM density map. A novel CTD-CTD interface at the local three-fold axis in the cryoEM map was confirmed by mutagenesis to be essential for function. More recently, the cryo-EM structure of the tube was solved at 8Å resolution and this cryo-EM structure allowed unambiguous modeling and refinement by large-scale molecular dynamics (MD) simulation, resulting in all-atom models for the hexamer-of-hexamer and pentamer-of-hexamer elements of spheroidal capsids. Furthermore, the 3D structure of a native HIV-1 core was determined by cryo-electron tomography (Cryo-ET), which in combination with MD simulations permitted the construction of a realistic all-atom model for the entire capsid, based on the 3D authentic core structure.