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.
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