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Albany 2013: Book of Abstracts

category image Albany 2013
Conversation 18
June 11-15 2013
©Adenine Press (2012)

Refinement of Force Field Torsion Parameters for Nucleic Acids Based on Inclusion of Conformation-Dependent Solvation Effects

Accurate representation of nucleic acids in molecular dynamics simulations depends critically on the quality of the applied empirical force field. Among force field terms, the torsion parameters are known to strongly influence the conformational equilibria and molecular structures. Unfortunately, past several years witnessed severe problems in describing the torsion space in nucleic acids by current force fields and more problems continue emerging. In an attempt for improvement, we suggested a novel parameterization procedure that incorporates some previously neglected solvation-related effects, which proved to be essential for obtaining accurate torsion profiles. The suggested approach avoids double counting of solvation effects and provides parameters that may be used in combination with any of the widely used non-polarizable discrete solvent models or with the continuum solvent models.

Improvements are demonstrated for the latest AMBER force field for RNA simulations, ff10, which incorporates parameters for the glycosidic torsion (χOL3) developed by us using the above described procedure (Zgarbová et al. 2011, Banáš et al. 2010). Resulting parameters are verified by extensive molecular dynamics simulations of canonical RNA duplexes and RNA hairpin loops. We show that our modification removes overstabilization of the high-anti region found in the ff99 force field and thus prevents formation of undesirable ‘ladder-like’ structural distortions in RNA simulations.

In addition, we applied our parameterization approach to development of the glycosidic torsion in DNA (χOL4). This refinement focuses on adjusting description of the syn region and syn-anti balance of the χ potential. This modification exhibits a notable improvement of the description of the antiparallel G-DNA stem, which was not modeled correctly by the current ff99 force field (Krepl et al. 2012).

The authors gratefully acknowledge the support by the Operational Program Research and Development for Innovations - European Regional Development Fund (project CZ.1.05/2.1.00/03.0058), the Operational Program Education for Competitiveness - European Social Fund (project CZ.1.07/2.3.00/20.0017), and Integration of Regional Centre of Advanced Technologies and Materials into International Networks of Nanotechnological and Optical Research (project CZ.1.07/2.3.00/20.0058).

References

    M. Zgarbová, et al. (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.

    P. Banáš, et al. (2010). Performance of Molecular Mechanics Force Fields for RNA Simulations: Stability of UUCG and GNRA Hairpins. J. Chem. Theory Comput. 6, 3836-3849.

    M. Krepl, et al. (2012). Reference Simulations of Noncanonical Nucleic Acids with Different chi Variants of the AMBER Force Field: Quadruplex DNA, Quadruplex RNA, and Z-DNA. J. Chem. Theory Comput. 8, 2506-2520.


Marie Zgarbová1
Michal Otyepka1
Pavel Banáš1
F. Javier Luque2
Thomas E. Cheatham, III3
Jiří Šponer4
Petr Jurečka1

1Regional Centre of Advanced Technologies and Materials, Department of Physical Chemistry
Faculty of Science
Palacky University
17. listopadu 12
77146 Olomouc, Czech Republic
2Department de Fisicoquímica and Institut de Biomedicina (IBUB)
Facultat de Farmàcia, Universitat de Barcelona
Avgda Diagonal 643
Barcelona 08028, Spain
3Department of Medicinal Chemistry
College of Pharmacy
University of Utah
Salt Lake City, Utah
United States
4Institute of Biophysics
Academy of Sciences of the Czech Republic
Královopolská 135
612 65 Brno, Czech Republic

Ph: (+420) 585 634 766
Fx: (+420) 585 634 761
marie.zgarbova@upol.cz
petr.jurecka@upol.cz