Fall 2015 Research Projects
High-Resolution Atomistic Simulations and Experimental Characterizations of CENP-A/H3 Hybrid Nucleosomes
Mary Pitman, Chemistry, University of Maryland
All eukaryotic cells undergo mitosis, in which newly replicated daughter DNA chromatids are equally segregated to the two opposite poles of the dividing cell. This process is wholly dependent on specialized chromatin containing the histone protein CENP-A. This protein has been reported to be over-expressed and mislocalized in cancer cells, partnering with inappropriate proteins. Thus, understanding the mechanical basis for CENP-A's unique function in the native and cancer state are fundamental questions in biology. Our project aims to use cutting edge cross-disciplinary tools such as all-atom simulations, using major supercomputing resources, coupled to high speed nano-imaging to visualize molecular changes in CENP-A in the native vs. cancer state.
A combined computational and experimental approach towards the design of a novel next-generation multivalent HER3-sequestration cancer therapy
John Schardt, Bioengineering, University of Maryland
Dysregulation of signaling between protein ligands and their cell surface receptors is a primary cause of tumor growth and metastasis in many cancers. One example of this phenomenon, which is especially prevalent in breast cancer, is the overexpression of the receptor HER3 leading to increased dimerization of HER3 with another receptor, HER2, on the surface of cancer cells, resulting in pro-neoplastic effects. We have pioneered a strategy, HER3 sequestration, that utilizes engineered multivalent HER3 ligands to trap HER3 into configurations that prevent its interaction with HER2, thus inhibiting pro-neoplastic signaling. The goal of the proposed research is to employ computational protein design and cancer biology experimental approaches to better understand and enhance HER3 sequestration towards the development of a novel cancer therapeutic.