My group focuses on developing novel force- and magnetic-based techniques for biomedical research. We have developed force-induced remnant magnetization spectroscopy (FIRMS) that distinguishes noncovalent bonds based on their rupture forces. With 2-3 pN force resolution, DNA duplexes with a single basepair difference can be clearly resolved; protein bonds have been revealed to have different binding strength on the cell surface compared to the flat surface. Recently, we invented the super-resolution force spectroscopy (SURFS), which exerts acoustic radiation force onto magnetically labeled molecular bonds to achieve unprecedented force resolution and hence bond specificity. With sub-piconewton (10^-12 Newton) resolution, intermolecular bonds with a single hydrogen bond difference can be distinguished. For nucleic acids, SURFS can reach half-nucleotide resolution from both ends. This invention allows the design of DNA rulers to precisely determine the position and movement of nucleic acids during their biological functions. No other techniques can provide the same resolution.
In collaboration with Prof. Yuhong Wang (Department of Biology and Biochemistry, University of Houston), we have applied our techniques to investigate the ribosomal translocation and frameshifting. We have resolved the multiple frameshifting steps that occurs when the ribosome translocates on a slippery mRNA sequence GA7G. We have also revealed a looped mRNA configuration during translocation that was trapped by antibiotics. In addition, we have applied a series of DNA duplexes as force rulers to quantify the substantial mechanical force generated by the translocase EF-G during it catalysis of ribosomal translocation. This power stroke, on the order of 90 pN, can be altered by structural modification or antibiotics.
The following are representative publications:
a. Jia, H., Wang, Y. & Xu, S.-J. Super-resolution force spectroscopy reveals ribosomal motion at sub-nucleotide steps. Chem. Commun. 54, 5883-5886 (2018).
b. Heng, Y., Xu, S.-J. & Wang, Y. Capturing the “mRNA looping” intermediate state during ribosome translocation by dual ruler assay. RNA Biol. 15, 1392-1398 (2018).
c. Jia, H., Tsai, T.-W. & Xu, S.-J. Probing drug-DNA interactions using super-resolution force spectroscopy. Appl. Phys. Lett. 113, 193702 (2018).
d. Tsai, T.-W., Yang, H., Yin, H., Xu, S.-J. & Wang, Y. High-efficiency “-1” and “-2” ribosomal frameshiftings revealed by force spectroscopy. ACS Chem. Biol. 12, 1629-1635 (2017).
e. Yao, L., Li, Y., Tsai, T.-W., Xu, S.-J. & Wang, Y. Noninvasive measurement of the mechanical force generated by motor protein EF-G during ribosome translocation. Angew. Chem. Int. Ed. 52, 14041-14044 (2013).