The research activities of the Molecular Modeling and Bioinformatics project can be grouped into four categories. (1) Study of forces that govern the stability of and interaction between protein molecules: We study hydrophobic effect and, more generally, solvent effect by statistical mechanical techniques. The knowledge and the insights gained from these studies are used to develop potential functions that can be used in ab initio protein folding, protein stability, protein engineering, and protein-protein and protein-ligand interaction studies. (2) Protein structure classification and fold recognition: We devised a new protein structure comparison procedure, which we use to classify protein structures. The classified protein structure database is used to gain an overview of the universe of protein structures and to study the architecture of protein structures. We also devised a new """"""""threading"""""""" potential based on a pair-to-pair amino acid comparisons. We will use both the classified protein structure database and the new threading potential to parse a protein into domains, to classify these domains into different structural groups, and to develop a more powerful protein fold recognition tool. (3) Immunotoxin engineering: Immunotoxins are hybrid molecules made by connecting an antibody Fv domain and a bacterial toxin. Such molecules can be used to kill specific cells such as cancer cells or the HIV infected cells. The Molecular Biology Section of this Laboratory has developed several of these molecules as anti-cancer agents, some of which are now in or at the end of the phase I clinical trial stage. In collaboration with the Molecular Biology Section, we examine these molecules and design mutations that will enhance the antigen binding, improve stability and yield, reduce immune response and reduce non-specific toxicity. The designs are tested experimentally by the Molecular Biology Section. (4) Gene discovery: In collaboration with the Molecular Biology Section, we have found some dozen new genes that are nearly specifically expressed in prostate or breast. The new gene discovery process begins with a list of EST clusters that we generate along with their tissue specificity data. For some of these, the structure of the product protein could be modeled, which gives information on possible biological function of the protein. We are now working on a new EST clustering method based on their alignment to the human genome sequence and on mining information from a new EST library from breast and prostate tumor cell lines that was made by the Molecular Biology Section.

Agency
National Institute of Health (NIH)
Institute
Division of Basic Sciences - NCI (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC008759-11
Application #
6762081
Study Section
(LMB)
Project Start
Project End
Budget Start
Budget End
Support Year
11
Fiscal Year
2002
Total Cost
Indirect Cost
Name
Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Das, Sudipto; Hahn, Yoonsoo; Walker, Dawn A et al. (2008) Topology of NGEP, a prostate-specific cell:cell junction protein widely expressed in many cancers of different grade level. Cancer Res 68:6306-12
Hahn, Yoonsoo; Jeong, Sangkyun; Lee, Byungkook (2007) Inactivation of MOXD2 and S100A15A by exon deletion during human evolution. Mol Biol Evol 24:2203-12
Das, Sudipto; Hahn, Yoonsoo; Nagata, Satoshi et al. (2007) NGEP, a prostate-specific plasma membrane protein that promotes the association of LNCaP cells. Cancer Res 67:1594-601
Grigoryev, Dmitry N; Ma, Shwu-Fan; Shimoda, Larissa A et al. (2007) Exon-based mapping of microarray probes: recovering differential gene expression signal in underpowered hypoxia experiment. Mol Cell Probes 21:134-9
Bera, Tapan K; Saint Fleur, Ashley; Lee, Yoomi et al. (2006) POTE paralogs are induced and differentially expressed in many cancers. Cancer Res 66:52-6
Hahn, Yoonsoo; Lee, Byungkook (2006) Human-specific nonsense mutations identified by genome sequence comparisons. Hum Genet 119:169-78
Sam, Vichetra; Tai, Chin-Hsien; Garnier, Jean et al. (2006) ROC and confusion analysis of structure comparison methods identify the main causes of divergence from manual protein classification. BMC Bioinformatics 7:206
Hahn, Yoonsoo; Bera, Tapan K; Pastan, Ira H et al. (2006) Duplication and extensive remodeling shaped POTE family genes encoding proteins containing ankyrin repeat and coiled coil domains. Gene 366:238-45
Egland, Kristi A; Liu, Xiu Fen; Squires, Stephen et al. (2006) High expression of a cytokeratin-associated protein in many cancers. Proc Natl Acad Sci U S A 103:5929-34
Hahn, Yoonsoo; Lee, Byungkook (2005) Identification of nine human-specific frameshift mutations by comparative analysis of the human and the chimpanzee genome sequences. Bioinformatics 21 Suppl 1:i186-94

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