Computational Modeling of Varying Nucleophile Activity on the RNA Cleavage Transition State
Jennifer Andre, Aastha Chokshi, Daniel Greenberg, Jay Karandikar, Steven Kunis, Joshua Loughran, Elena Malloy, David Mazumder, Dushyant Patel, Jeffrey Wu, Grace Zhang
Advisor: Adam Cassano
Assistant: Zack Vogel
ABSTRACT
Density functional theory calculations were performed on simplified models of RNA, simulating RNA cleavage. A total of four versions of the model were examined, varying by the electronegativity of their 2’ groups, which affected the electron density of the nucleophile. The basis set DFT 6-31++G(d,p) and B3LYP method were used to optimize the geometries and vibrational frequencies. Molecular energies were calculated with the basis set DFT 6-311++G(3df,2p) with both the B3LYP and MPWB1K methods. The structure of the transition state was found by conducting optimization-frequency calculations on the reactant and products of the cleavage reaction, and the effects of the varied nucleophilic potency were measured in the differences in the structure of the transition state and in the reaction rate constant. As the electronegativity of the fluorinated methyl group increases, the transition state becomes more dissociative with respect to the bond between the phosphorus and the leaving group. The addition of fluorine atoms also caused the free energy of activation of the reaction to increase and the rate constant to decrease, demonstrating that the increased dissociative nature of the transition state raised the required energy for the reaction to progress.