Very few macromolecules act as distinct units; rather, they are often components of much larger and more sophisticated molecular 'machines.' I am interested in understanding the mechanics of large scale conformational re-arrangements, and how these are effected in the cellular environment.
The field of cryo-Electron Tomography (cryoET) has greatly benefited from adaptations of techniques from Single Particle EM (SPR). Unlike SPR, cryoET can be used to interrogate irregular structures. Although lacking global symmetry, most biological structures possess some degree of internal symmetry, which I am currently working to exploit in order to push the attainable resolution of heterogeneous macromolecular complexes using cryoET beyond 10Å.
At this resolution, the EM density map may be used as a constraint for molecular dynamics simulation, allowing higher resolution structures of component molecules to be reliably placed into their biologically relevant context.
I am also adapting a technique commonly used in Materials Science -- Focused Ion Beam milling -- to cryo-prepared EM samples. This will open up cryoET to structures that are of great interest (HIV infected cells for example) but are currently inaccessible due to their thickness causing multiple scattering events which, degrades the resolution of transmission EM.
B.Sc. in Physics, Penn State University, University Park, PA
PhD Advisor: Dr. Peijun Zhang
Department of Structural Biology
University of Pittsburgh School of Medicine
2050 Biomedical Science Tower 3 (BST3)
3501 5th Avenue, Pittsburgh PA 15260
- Fu X, Himes BA, Ke D, Rice WJ, Ning J, Zhang P. (2014) Controlled bacterial lysis for electron tomography of native cell membranes. Structure 22(12):1875-82
- Cassidy CK, Himes BA, Alvarez FJ, Ma J, Zhao G, Perilla JR, Schulten K, Zhang P (2015) CryoEM and computer simulations reveal a novel kinase conformational switch in bacterial chemotaxis signaling. Elife: pii: e08419. doi: 10.7554/eLife.08419
- Liu C, Perilla JR, Ning J, Lu M, Hou G, Ramalho R, Himes BA, Zhao G, Bedwell GJ, Byeon IJ, Ahn J, Gronenborn AM, Prevelige PE, Rousso I, Aiken C, Polenova T, Schulten K, Zhang P. (2016) Cyclophilin A stabilizes the HIV-1 capsid through a novel non-canonical binding site. Nat Commun. 7:10714
- Ning J, Erdemci-Tandogan G, Yufenyuy EL, Wagner J, Himes BA, Zhao G, Aiken C, Zandi R, Zhang P. In Vitro Protease Cleavage and Computer Simulations Reveal the HIV-1 Capsid Maturation Pathway. Nature Communications 7 (2016): 13689.
- Cassidy CK, Himes BA, Luthey-Schulten Z, Zhang P. CryoEM-based hybrid modeling approaches for structure determination. Curr Opin Microbiol. 2017 Nov 3;43:14-23