Albany 2015:Book of Abstracts
June 9-13 2015
©Adenine Press (2012)
Benchmark of Amber ff12SB force field by comparison of estimated hairpin loop folding stabilities to experiments
The accuracy of the force field determines the ability of molecular dynamic simulations to characterize a system. We investigated the ability of the Amber force field ff12SB (Cheatham, et al., 1999; Wang, et al., 2000; Perez, et al., 2007; Zgarbova, et al., 2011) to predict relative free energy changes of RNA hairpin formation. 12-mer hexaloop RNA hairpins: r(GGCGUAAUAGCC) (Fountain et al., 1996), r(GCGUUAAUUCGC) (PDB code: 1HS3) (Zhang et al., 2001) and r(CGACAGUGCUCG) (PDB code: 1AQO) (Addess et al., 1997) were studied. For each hairpin, four independent 700-ns simulations were performed. The potential of mean force (pmf) of stretching the hairpins from the native state (O5' at 5'-end to O3' at 3'-end distance: ∼17 Å ) to an extended conformation (end-to-end distance: 60 Å) was estimated by umbrella sampling. Each hairpin stem-loop was sampled with four independent simulations, with a total sampling of 128 µs each.
The PMFs were compared with a combination of experimental melting data and nearest neighbor parameters using a thermodynamic cycle. We find that the differences of free energy change of transitions between the hairpin sequences (ΔΔG°) in the comparison of simulation data and experimental data, are approximately 1.1 kcal/mol. This suggests that the Amber force field ff12SB is able to rank folding free energies of RNA hairpins.
J. M. Wang, P. Cieplak and P. A. Kollman (2000) How well does a restrained electrostatic potential (RESP) model perform in calculating conformational energies of organic and biological molecules? J. Comput. Chem., 21, 1049- 1074.
A. Perez, I. Marchan, D. Svozil, J. Sponer, T. E. Cheatham, and C. A. Laughton and M. Orozco (2007) Refinenement of the AMBER force field for nucleic acids: Improving the description of alpha/gamma conformers Biophys. J., 92, 3817- 3829.
M. Zgarbova, M. Otyepka, J. Sponer, A. Mladek, P. Banas, T. E. Cheatham, P. Jurecka (2011) Refinement of the Cornell et al. nucleic acids force field based on reference quantum chemical calculations of glycosidic torsion profiles J. Chem. Theory Comput., 7, 2886- 2902.
M. A. Fountain, M. J. Serra, T. R. Krugh, and D. H. Turner (1996) Structural Features of a Six-Nucleotide RNA Hairpin Loop Found in Ribosomal RNA. Biochemistry, 35, 6539-6548.
H. Zhang, M. A. Fountain and T. R. Krugh (2001) Structural characterization of a six-nucleotide RNA hairpin loop found in Escherichia coli, r(UUAAGU). Biochemistry, 40, 9879-9886.
K. J. Addess, J. P. Basilion, R. D. Klausner, T. A. Rouault and A. Pardi (1997) Structure and dynamics of the iron responsive element RNA: implications for binding of the RNA by iron regulatory binding proteins. J. Mol. Biol., 274, 72-83.
Department of Biochemistry and Biophysics