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Optimization of an AMBER Force Field for the Artificial Nucleic Acid, LNA, and Benchmarking with NMR of L(CAAU)

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      Abstract

      Locked Nucleic Acids (LNAs) are RNA analogues with an O2′-C4′ methylene bridge which locks the sugar into a C3′-endo conformation. This enhances hybridization to DNA and RNA, making LNAs useful in microarrays and potential therapeutics. Here, the LNA, L(CAAU), provides a simplified benchmark for testing the ability of molecular dynamics (MD) to approximate nucleic acid properties. LNA χ torsions and partial charges were parametrized to create AMBER parm99_LNA. The revisions were tested by comparing MD predictions with AMBER parm99 and parm99_LNA against a 200 ms NOESY NMR spectrum of L(CAAU). NMR indicates an A-Form equilibrium ensemble. In 3000 ns simulations starting with an A-form structure, parm99_LNA and parm99 provide 66% and 35% agreement, respectively, with NMR NOE volumes and 3J-couplings. In simulations of L(CAAU) starting with all χ torsions in a syn conformation, only parm99_LNA is able to repair the structure. This implies methods for parametrizing force fields for nucleic acid mimics can reasonably approximate key interactions and that parm99_LNA will improve reliability of MD studies for systems with LNA. A method for approximating χ population distribution on the basis of base to sugar NOEs is also introduced.

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          We describe the development, current features, and some directions for future development of the Amber package of computer programs. This package evolved from a program that was constructed in the late 1970s to do Assisted Model Building with Energy Refinement, and now contains a group of programs embodying a number of powerful tools of modern computational chemistry, focused on molecular dynamics and free energy calculations of proteins, nucleic acids, and carbohydrates. (c) 2005 Wiley Periodicals, Inc.
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            Author and article information

            Affiliations
            []Department of Chemistry, University of Rochester , Rochester, New York 14627, United States
            []Department of Chemistry, Northwestern University , Evanston, Illinois 60208, United States
            []Department of Biochemistry and Biophysics, Univeristy of Rochester , Rochester, New York 14642, United States
            [§ ]University of Rochester Center for Integrated Research Computing, Rochester, New York 14627, United States
            []Institute of Bioorganic Chemistry, Polish Academy of Sciences , 61-704 Poznan, Poland
            Author notes
            Journal
            J Phys Chem B
            J Phys Chem B
            jp
            jpcbfk
            The Journal of Physical Chemistry. B
            American Chemical Society
            1520-6106
            1520-5207
            30 December 2013
            06 February 2014
            : 118
            : 5
            : 1216-1228
            3917691
            10.1021/jp408909t
            Copyright © 2013 American Chemical Society
            Funding
            National Institutes of Health, United States
            Categories
            Article
            Custom metadata
            jp408909t
            jp-2013-08909t

            Physical chemistry

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