Overview
The Bevilacqua Lab has been involved in computational chemistry in many different ways. These efforts fall into three distinct areas:
(1) Statistical Thermodynamics. (2) Bioinformatics and Cheminformatics. (3) Molecular Dynamics and QM-MM. Computational work interests us because it provides deep insight into experiments and thus biology. The approaches described below have helped us develop new hypotheses that have been tested by experiments, as well as been informed by experiments. We adhere to words of Richard Feynman who stated, “The test of all knowledge is experiment.”
(1) Statistical Thermodynamics. We have addressed the function of RNAs by enumerating the various states that a ribozyme can occupy into a partition function formalism and used this to describe RNA rate-pH profiles and coupling of RNA folding and proton binding. These approaches have provided insight into these systems by deconvoluting complex averaged signals into components that provide molecular insight. The approach is one of deriving general equations according to binding and kinetic models and simulating data [1] followed by fitting to models [2].
(2) Bioinformatics and Cheminformatics. Rich information lies in datasets that can be extracted by computational approaches. Bioinformatics refers to the process of writing scripts and computational pipelines to extract trends from genomics data that we generate from our Structure-seq approaches. These approaches provide insight into how RNA structure can regulate gene expression and how that changes during diverse abiotic stresses [3]. Cheminformatics again refers to the process of writing scripts and computational pipelines, but here the trends are extracted from molecular data, typically crystal structures of RNAs. These approaches provide insight into how RNA structure sets up to drive catalysis in conserved ways [4].
(3) Molecular Dynamics and QM-MM. These are methods that are also atomistic in nature, similar to Cheminformatics and Statistical Thermodynamics, but with the important difference that they evolve with time in the presence of a force field. These studies offer the ability to discern the effect of environment and functional groups on the pKa of a reaction, or to look at pathways for cleavage [5]. This work continues to be done in collaboration with the Hammes-Schiffer lab, but is now performed by Bevilacqua lab members.
Methods Applied
Statistical Thermodynamics: Derivation of equations from simple models; simulations; data fitting; iterating with experiments. Bioinformatics and Cheminformatics: Programming in Python and R, PyMol analysis. Molecular Dynamics and QM/MM: Programming in Python, R, Gaussian, and Amber, calculating pKas and reaction trajectories.
Group Members
Phil Bevilacqua Catherine Douds Elizabeth Jolley Kobie Kirvin Lauren McKinley McCauley Meyer Jacob Sieg
Collaborators
Sharon Hammes-Schiffer (Yale University)
Five Recent Publications
- 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]
- Frankel, E. A., Strulson, C., Keating, C. D., and Bevilacqua, P. C. “Cooperative interactions in the hammerhead ribozyme drive pKa shifting of G12 and its stacked base C17.” Biochemistry 56, 2537-2548 (2017). [PubMed]
- Tack, D. C., Tang, Y., Ritchey, L. E., Assmann, S. M., and Bevilacqua, P. C. StructureFold2: Bringing chemical probing data into the computational fold of RNA structural analysis, Methods 143, 12-15. (2018) [PubMed].
- 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].
- 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 Article
- 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].