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Geometrical and Electronic Structure Variability of the Sugar−phosphate Backbone in Nucleic Acids

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Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Flemingovo náměstí 2, 166 10, Prague 6, Czech Republic, Institute of Biophysics, Academy of Sciences of the Czech Republic, Královopolská 135, 612 65 Brno, Czech Republic, Molecular Modeling and Bioinformatics Unit, Institut de Recerca Biomèdica, Parc Científic de Barcelona, Josep Samitier 1-5, Barcelona 08028, Spain, Departament de Bioquímica i Biologia Molecular, Universitat de Barcelona, Avgda Diagonal 645, Barcelona 08028, Spain, Barcelona Supercomputing Center, Jordi Girona 31, Edifici Torre Girona, Barcelona 08034, Spain, Department of Medicinal Chemistry and Department of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, University of Utah, Salt Lake City, Utah 84112, Department of Physical Chemistry and Institute of Biomedicine (IBUB), Faculty of Pharmacy, University of Barcelona, Avenida Diagonal 643, 08028 Barcelona, Spain, and Computational Biology Program, Barcelona Supercomputer Center, Jordi Girona 29, Edifici Nexus II, Barcelona 08034, Spain
* Corresponding author. E-mail: [email protected]
†Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic.
‡Institute of Biophysics, Academy of Sciences of the Czech Republic.
§Parc Científic de Barcelona.
∥Departament de Bioquímica i Biologia Molecular, Universitat de Barcelona.
⊥Barcelona Supercomputing Center, Edifici Torre Girona.
#University of Utah.
∇Faculty of Pharmacy, University of Barcelona.
○Barcelona Supercomputer Center, Edifici Nexus II.
Cite this: J. Phys. Chem. B 2008, 112, 27, 8188–8197
Publication Date (Web):June 18, 2008
Copyright © 2008 American Chemical Society

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    The anionic sugar−phosphate backbone of nucleic acids substantially contributes to their structural flexibility. To model nucleic acid structure and dynamics correctly, the potentially sampled substates of the sugar−phosphate backbone must be properly described. However, because of the complexity of the electronic distribution in the nucleic acid backbone, its representation by classical force fields is very challenging. In this work, the three-dimensional potential energy surfaces with two independent variables corresponding to rotations around the α and γ backbone torsions are studied by means of high-level ab initio methods (B3LYP/6-31+G*, MP2/6-31+G*, and MP2 complete basis set limit levels). The ability of the AMBER ff99 [Wang, J. M.; Cieplak, P.; Kollman, P. A. J. Comput. Chem.2000, 21, 1049−1074] and parmbsc0 [Perez, A.; Marchan, I.; Svozil, D.; Šponer, J.; Cheatham, T. E.; Laughten, C. A.; Orozco, M. Biophys. J.2007, 92, 3817−3829] force fields to describe the various α/γ conformations of the DNA backbone accurately is assessed by comparing the results with those of ab initio quantum chemical calculations. Two model systems differing in structural complexity were used to describe the α/γ energetics. The simpler one, SPM, consisting of a sugar and methyl group linked through a phosphodiester bond was used to determine higher-order correlation effects covered by the CCSD(T) method. The second, more complex model system, SPSOM, includes two deoxyribose residues (without the bases) connected via a phosphodiester bond. It has been shown by means of a natural bond orbital analysis that the SPSOM model provides a more realistic representation of the hyperconjugation network along the C5′−O5′−P−O3′−C3′ linkage. However, we have also shown that quantum mechanical investigations of this model system are nontrivial because of the complexity of the SPSOM conformational space. A comparison of the ab initio data with the ff99 potential energy surface clearly reveals an incorrect ff99 force-field description in the regions where the γ torsion is in the trans conformation. An explanation is proposed for why the α/γ flips are eliminated so successfully when the parmbsc0 force-field modification is used.

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    The characteristics of the CH···O HBs, solvation free energies, NBO analysis results, SPSOM model-system charges, and geometries (xyz coordinates) of all the investigated conformations on the ff99, parmbsc0, B3LYP/6-31+G*, and MP2/6-31+G* PESs. This material is available free of charge via the Internet at

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