Protein and deoxyribonucleic acid (DNA) interactions are ubiquitous and play vital roles in controlling functional cellular systems and abnormal cell transformations (e.g., tumor progression). Upon binding, the DNA and/or proteins frequently undergo conformational changes due to the requirement of new complex formation. We hypothesize that these """"""""molecular mechanics"""""""" can be probed with a man-made molecular accordion consisting of a string of fluorescent chromophores linked with foldable hinges. Molecular conformation changes will exert forces on the accordion, thereby tuning the fluorescent emission colors. As a first step, we will use solid phase synthesis to construct molecular accordions consisting of fluorescent chromophores and DNA sequences known to promote protein binding. The accordion-protein interactions will be carried out in vitro with wellcontrolled parameters.
Our specific aims are to design and synthesize molecular accordions with multiple fluorescent chromophores on DNA and to apply fluorescent spectroscopy and microscopy in controlled conditions to gauge protein-DNA interactions. In particular, we will start with HMGA1 protein, which is a diagnostic marker for neoplastic transformation and metastatic potential of many type cancers. In this project, we plan to determine the parameters that define the scope of the formation of protein-DNA-accordion complex; these parameters will be essential for proposed future in vivo applications of molecular accordions. Our long-term objectives are to use these molecular accordions to probe regulatory events in vivo and to further our understanding of abnormal cell transformations underlying molecular mechanism of diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM065306-01A1
Application #
6732274
Study Section
Special Emphasis Panel (ZRG1-BECM (01))
Program Officer
Edmonds, Charles G
Project Start
2003-09-30
Project End
2008-08-31
Budget Start
2003-09-30
Budget End
2004-08-31
Support Year
1
Fiscal Year
2003
Total Cost
$242,540
Indirect Cost
Name
Washington State University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
041485301
City
Pullman
State
WA
Country
United States
Zip Code
99164
Shaller, Andrew D; Wang, Wei; Li, Aixiao et al. (2011) Sequence-controlled oligomers fold into nanosolenoids and impart unusual optical properties. Chemistry 17:8350-62
Tian, Zhiyuan; Wu, Wuwei; Li, Alexander D Q (2009) Photoswitchable fluorescent nanoparticles: preparation, properties and applications. Chemphyschem 10:2577-91
Zhuang, Jiaqi; Shaller, Andrew D; Lynch, Jared et al. (2009) Cylindrical superparticles from semiconductor nanorods. J Am Chem Soc 131:6084-5
Wu, Wuwei; Wan, Wei; Li, Alexander D Q (2009) The nuclear architectural protein HMGA1a triggers receptor-mediated endocytosis. J Cell Biochem 108:791-801
Tian, Zhiyuan; Wu, Wuwei; Wan, Wei et al. (2009) Single-chromophore-based photoswitchable nanoparticles enable dual-alternating-color fluorescence for unambiguous live cell imaging. J Am Chem Soc 131:4245-52
Han, Jason J; Shaller, Andrew D; Wang, Wei et al. (2008) Architecturally diverse nanostructured foldamers reveal insightful photoinduced single-molecule dynamics. J Am Chem Soc 130:6974-82
Hu, Dehong; Tian, Zhiyuan; Wu, Wuwei et al. (2008) Photoswitchable nanoparticles enable high-resolution cell imaging: PULSAR microscopy. J Am Chem Soc 130:15279-81
Shaller, Andrew D; Wang, Wei; Gan, Haiyang et al. (2008) Tunable molecular assembly codes direct reaction pathways. Angew Chem Int Ed Engl 47:7705-9
Wang, Wei; Shaller, Andrew D; Li, Alexander D Q (2008) Twisted perylene stereodimers reveal chiral molecular assembly codes. J Am Chem Soc 130:8271-9
Wan, Wei; Wang, Wei; Li, Alexander D Q (2008) HMGA1a protein unfolds or refolds synthetic DNA-chromophore hybrid polymers: a chaperone-like behavior. Chembiochem 9:304-11

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