Book of Abstracts: Albany 2011

category image Albany 2011
Conversation 17
June 14-18 2011
©Adenine Press (2010)

Refinement of the AMBER Force Field for Stable Simulations of RNA Systems and Its Application to RNA Hairpin Loops and A-RNA stems

The RNA hairpin loops represent important RNA motifs with nominally unpaired single strand segment folded on itself to terminate an A-RNA double helix. The most frequently observed hairpin loops with indispensable biological functions are tetraloops (TLs) having four loop bases to cap the A-RNA stem. Among all tetraloops, 5’-UNCG-3’ and 5’-GNRA-3’ tetraloop families are the most abundant. The 5’-GNRA-3’ tetraloops are able to make an interaction with tetraloop receptors. This interaction is involved in numerous structurally important tertiary contacts in folded RNAs such as e.g. glmS riboswitch.1-3 The 5’-UNCG-3’ tetraloops belong to the most thermodynamic stable RNA structural motifs, they reveal very limited structural variability and most likely play a crucial role in nucleation during RNA global folding.

Molecular dynamics is a powerful theoretical method that can efficiently complement and extend the experimental data and provide unique insight into structural dynamics on the atomistic level. However, the quality of molecular dynamic simulations is reasonably compromised by imperfections in empirical potential (also called force field).4, 5 Recently, we investigated structural dynamics of three representatives (UUCG, GAGA and GAAA) of UNCG and GNRA TL families.6 We utilized all currently available force fields that are able to reasonably describe structural dynamics of nucleic acids: three variants of Cornell et al. force fields ff94, ff99 and ff99bsc0 (known as AMBER force fields) and CHARMM27 force field.5 The simulations revealed several significant structural distortions documenting that none of these standard force fields is able to correctly describe structural dynamics of studied tetraloops. Namely transformation of A-RNA stems carrying tetraloop into sense-less ladder-like structures in AMBER simulations was the most painful. Unfortunately, the ladder-like structures were also identified in simulations of other folded RNA systems, e.g. hairpin ribozyme.7

To better understand the force fields imbalances corresponding to artificial instability of tetraloops in molecular dynamic simulations, we performed simulations with Cornell et al. force fields in combination with our recently developed reparameterizations of glycosidic torsion.6 We found that this reparameterized glycosidic torsion reasonably improved description of the tetraloops, mainly in syn region of glycosidic torsion in the UNCG tetraloop and balance between anti/high-anti region affecting the stability of A-RNA stems bearing tetraloops that were prone to progressive degradation toward sense-less ladder-like structures in standard AMBER force fields.7 The best performance in tetraloop and A-RNA stems simulations was achieved in combination of glycosidic torsion correction with the bsc0 parameterization of the α/γ angles.

  1. P. Banas, N. G. Walter, J. Sponer and M. Otyepka, J Phys Chem B 114, 8701-8712, (2010).
  2. J. C. Cochrane, S. V. Lipchock and S. A. Strobel, Chem Biol 14, 95-103, (2007).
  3. D. J. Klein and A. R. Ferre-D'Amare, Science 313, 1752-1756, (2006).
  4. P. Banas, P. Jurecka, N. G. Walter, J. Sponer and M. Otyepka, Methods 49, 202-216, (2009).
  5. M. A. Ditzler, M. Otyepka, J. Sponer and N. G. Walter, Acc Chem Res 43, 40-47, (2010).
  6. P. Banas, D. Hollas, M. Zgarbova, P. Jurecka, M. Orozco, T. E. Cheatham, J. Sponer and M. Otyepka, J Chem Theory Comput 6, 3836-3849, (2010).
  7. V. Mlynsky, P. Banas, D. Hollas, K. Reblova, N. G. Walter, J. Sponer and M. Otyepka, J Phys Chem. B 114, 6642-6652, (2010).

Pavel Baná1
Daniel Hollas1
Marie Zgarbová1
Petr Jurečka1
Modesto Orozco2
Thomas E. Cheatham III3
Jiří Šponer4
and Michal Otyepka1

1Regional Centre of Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science, Palacky University, Olomouc, Czech Republic
4Institute of Biophysics, Academy of Sciences of the Czech Republic, Brno, Czech Republic
2Departament de Bioquímica i Biología Molecular, Facultat de Biología, Barcelona, Spain
3Departments of Medicinal Chemistry, Pharmaceutical Chemistry and Pharmaceutics and Bioengineering, University of Utah, Salt Lake City, USA

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