The Bevilacqua Lab

RNA Chemistry and Biology

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Ribozyme Mechanism

Overview

NLPB of HDV active siteIn the early 1980’s, Tom Cech and Sidney Altman showed that RNA could act as an enzyme–a ‘ribozyme’–catalyzing the making and breaking of covalent bonds. This led to the 1989 Nobel Prize in Chemistry. The Bevilacqua lab helped establish roles for nucleobases in proton transfer, determination of driving forces for pKa shifting, and establishing multichannel pathways for RNA cleavage by a combination of experiments and classical and quantum mechanical theory. We are currently working in twister and related ribozymes to determine roles of metal ions, nucleobases, and cofactors in the mechanism of cleavage of the catalytic RNAs [1-5].  In addition, the lab is focused on how these RNAs fold under in vivo conditions.

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Methods Applied

Kinetics: hand-mixing, rapid-quench, stopped-flow, co-transcriptional; Isotope effects: solvent isotope, thio effects, proton inventory, metal ion rescue; Structural: crystallography, Raman crystallography, small-angle X-ray scattering (SAXS); Theory: MD, QM-MM

Group Members

McCauley Meyer   Lauren McKinley

Collaborators

Sharon Hammes-Schiffer (Yale University)
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Five Recent Publications

  1. Bevilacqua, P. C., Harris, M. E., Piccirilli, J. A., Gaines, C., Ganguly, A., Kostenbader, K., Ekesan, S., York D. M. An ontology for facilitating discussion of catalytic strategies of RNA-cleaving enzymes. ACS Chem. Biol. 14, 1068-1076 (2019)  [PubMed]
  2. Messina, K. J. & Bevilacqua, P. C. Cellular small molecules contribute to twister ribozyme catalysis. J. Am. Chem. Soc. 140, 10578-10582 (2018) [PubMed] (link to 50 free e-prints).
  3. Frankel, E. A. & Bevilacqua, P. C. “Complexity in pH-dependent ribozyme kinetics: Dark pKa shifts and wavy rate-pH profiles.” Biochemistry 57, 483-488 (2018). [PubMed]
  4. Seith, D., Bingaman, J. L., Veenis, A.J., Button, A.C., & Bevilacqua, P. C. “Elucidation of catalytic strategies of small nucleolytic ribozymes from comparative analysis of active sites.” ACS Catalysis 8, 314-327 (2018) [link] (link to 50 free e-prints).
  5. Bingaman, J. L., Zhang, S., Stevens, D. R., Yennawar, N. H., Hammes-Schiffer, S., Bevilacqua, P. C.  “GlcN6P Cofactor serves multiple catalytic roles in the glmS  ribozyme” Nat. Chem. Biol. 13, 439-445 (2017). [PubMed]

Review Articles

  1. Bevilacqua, PC, Bingaman, JL, Frankel, E A, Messina, K J, Seith, D D Key catalytic strategies in ribozymes, Chapter in “Catalysis in Chemistry and Biology”, Proceedings of the 24th International Solvay Conference in Chemistry: Catalysis in Chemistry and Biology. (2018) [Google Books].
  2. Golden, B. L., Hammes-Schiffer, S., Carey, P. R. & Bevilacqua, P. C. (2013). An integrated picture of HDV ribozyme catalysis. Biophysics of RNA Folding, Springer. [pdf]
  3. Bevilacqua, P. C. (2008). Proton Transfer in Ribozyme Catalysis. In Ribozymes and RNA Catalysis (Lilley, D. M. & Eckstein, F., eds.), pp. 11-36. Royal Society of Chemistry, Cambridge. [pdf]

Complete list of ribozyme publications (click here)

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