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Computational Approach to RNA-Protein Binding

One of the most prevalent neurologically degenerative diseases within the United States is frontotemporal lobular dementia (FTLD), which spontaneously occurs in individuals without discrimination for sex or age (Young et al. 2018). This disease, as well as other non-Tau induced neurodegenerative diseases, is believed to be implicated in errors in TAR (trans active response) Tar-DNA Binding Protein 43 kDa (TDP-43) behavior (Geser et al. 2009). While structural data exists for the individual domains of TDP-43 has been determined experimentally, the native structure of the full-length protein has yet to be determined due to the innate disorder and relatively large size of the protein. In addition, there have been very few studies focused on the computational analysis of the RNA Recognition Motifs (RRMs) bound to RNA; however, there have been binding assay experiments that have shown sequence specificity in TDP-43 binding affinity to RNA with uracil and guanine alternating repeats (Lukavsky et al.). Over the summer I used the AMBER Suite and HDOCK, both well-established computational programs for structural analysis, to observe how RNA that has been experimentally determined to be associated with TDP-43 binds to the RRM domains. From this analysis, a better understanding of the binding of nucleotides to the RRM domains can be obtained, and by coming to understand more about the binding function of this domain, potential experiments can take place to better understand the structure of the protein, the orientation of these domains within the protein, and what nucleotides bind best to these domains.

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