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Refinement of the AMBER Force Field for Nucleic Acids: Improving the Description of / Conformers

Alberto Pérez ^* , Iván Marchán ^* , Daniel Svozil  ^¶, Jiri Sponer  ^¶, Thomas E. Cheatham, III ^||, Charles A. Laughton ^** and Modesto Orozco ^*  

^* Molecular Modeling and Bioinformatics Unit, Institut de Recerca Biomèdica & Instituto Nacional de Bioinformática, Parc Científic de Barcelona, Barcelona 08028, Spain; Computational Biology Program, Barcelona Supercomputer Centre, Edifici Torre Girona, Barcelona 08028, Spain; Institute of Organic Chemistry and Biochemistry, Center for Biomolecules and Complex Molecular Systems, Academy of Sciences of the Czech Republic, 166 10 Prague 6, Czech Republic; Institute of Biophysics, Academy of Sciences of the Czech Republic, 612 65 Brno, Czech Republic; ^¶ Faculty of Science, Masaryk University, 611 37 Brno, Czech Republic; ^|| Departments of Medicinal Chemistry, Pharmaceutical Chemistry and Pharmaceutics and Bioengineering, University of Utah, Salt Lake City, Utah 84112; ^** School of Pharmacy and Centre for Biomolecular Sciences, University of Nottingham, Nottingham NG7 2RD, United Kingdom; and Departament de Bioquímica i Biología Molecular, Facultat de Biología, Universitat de Barcelona, Barcelona 08028, Spain

Correspondence: Address reprint request to Modesto Orozco, Molecular Modeling and Bioinformatics Unit, Institut de Recerca Biomèdica & Instituto Nacional de Bioinformática, Parc Científic de Barcelona, Barcelona 08028, Spain. E-mail: modesto{at}mmb.pcb.ub.es or modesto.orozco{at}bsc.es.

We present here the parmbsc0 force field, a refinement of the AMBER parm99 force field, where emphasis has been made on the correct representation of the / concerted rotation in nucleic acids (NAs). The modified force field corrects overpopulations of the / = (g+,t) backbone that were seen in long (more than 10 ns) simulations with previous AMBER parameter sets (parm94-99). The force field has been derived by fitting to high-level quantum mechanical data and verified by comparison with very high-level quantum mechanical calculations and by a very extensive comparison between simulations and experimental data. The set of validation simulations includes two of the longest trajectories published to date for the DNA duplex (200 ns each) and the largest variety of NA structures studied to date (15 different NA families and 97 individual structures). The total simulation time used to validate the force field includes near 1 µs of state-of-the-art molecular dynamics simulations in aqueous solution.

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