Refinement of empirical force fields for nucleic acids requires their extensive testing using as wide range of systems as possible. However, finding unambiguous reference data is not easy. In this paper, we analyze four systems which we suggest should be included in standard portfolio of molecules to test nucleic acids force fields, namely, parallel and antiparallel stranded DNA guanine quadruplex stems, RNA quadruplex stem, and Z-DNA. We highlight parameters that should be monitored to assess the force field performance. The work is primarily based on 8.4 μs of 100-250 ns trajectories analyzed in detail followed by 9.6 μs of additional selected back up trajectories that were monitored to verify that the results of the initial analyses are correct. Four versions of the Cornell et al. AMBER force field are tested, including an entirely new parmχ(OL4) variant with χ dihedral specifically reparametrized for DNA molecules containing syn nucleotides. We test also different water models and ion conditions. While improvement for DNA quadruplexes is visible, the force fields still do not fully represent the intricate Z-DNA backbone conformation.

Institute of Biophysics Academy of Sciences of the Czech Republic Kralovopolska 135 612 65 Brno Czech Republic

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Ditzler MA, Otyepka M, Sponer J, Walter NG. Acc Chem Res. 2010;43:40–47. PubMed PMC

Besseova I, Otyepka M, Reblova K, Sponer J. Phys Chem Chem Phys. 2009;11:10701–10711. PubMed

Gaillard T, Case DA. J Chem Theory Comput. 2011;7:3181–3198. PubMed PMC

Šponer J, Cang X, Cheatham TE., III Methods. in press.

Cornell WD, Cieplak P, Bayly CI, Gould IR, Merz KM, Ferguson DM, Spellmeyer DC, Fox T, Caldwell JW, Kollman PA. J Am Chem Soc. 1995;117:5179–5197.

Cheatham TE, III, Cieplak P, Kollman PA. J Biomol Struct Dyn. 1999;16:845–862. PubMed

Wang J, Cieplak P, Kollman PA. J Comp Chem. 2000;21:1049–1074.

Perez A, Marchan I, Svozil D, Sponer J, Cheatham TE, Laughton CA, Orozco M. Biophys J. 2007;92:3817–3829. PubMed PMC

Banas P, Hollas D, Zgarbova M, Jurecka P, Orozco M, Cheatham TE, Sponer J, Otyepka M. J Chem Theory Comput. 2010;6:3836–3849. PubMed PMC

Zgarbova M, Otyepka M, Sponer J, Mladek A, Banas P, Cheatham TE, Jurecka P. J Chem Theory Comput. 2011;7:2886–2902. PubMed PMC

Ode H, Matsuo Y, Neya S, Hoshino T. J Comput Chem. 2008;29:2531–2542. PubMed

Yildirim I, Stern HA, Kennedy SD, Tubbs JD, Turner DH. J Chem Theory Comput. 2010;6:1520–1531. PubMed PMC

Yildirim I, Kennedy SD, Stern HA, Hart JM, Kierzek R, Turner DH. J Chem Theory Comput. 2011;8:172–181. PubMed PMC

Foloppe N, MacKerell AD. J Comput Chem. 2000;21:86–104.

Denning EJ, Priyakumar UD, Nilsson L, Mackerell AD. J Comput Chem. 2011;32:1929–1943. PubMed PMC

Hart K, Foloppe N, Baker CM, Denning EJ, Nilsson L, MacKerell AD. J Chem Theory Comput. 2012;8:348–362. PubMed PMC

Cheatham TE, III, Miller JL, Fox T, Darden TA, Kollman PA. J Amer Chem Soc. 1995;117:4193–4194.

Cheatham TE, III, Kollman PA. J Amer Chem Soc. 1997;119:4805–4825.

Fadrna E, Spackova N, Stefl R, Koca J, Cheatham TE, Sponer J. Biophys J. 2004;87:227–242. PubMed PMC

Svozil D, Sponer JE, Marchan I, Perez A, Cheatham TE, 3rd, Forti F, Luque FJ, Orozco M, Sponer J. J Phys Chem B. 2008;112:8188–8197. PubMed

Mlynsky V, Banas P, Hollas D, Reblova K, Walter NG, Sponer J, Otyepka M. J Phys Chem B. 2010;114:6642–6652. PubMed PMC

Fadrna E, Spackova N, Sarzynska J, Koca J, Orozco M, Cheatham TE, Kulinski T, Sponer J. J Chem Theory Comput. 2009;5:2514–2530. PubMed

Spackova N, Sponer J. Nucleic Acids Res. 2006;34:697–708. PubMed PMC

Mladek A, Sponer JE, Kulhanek P, Lu XJ, Olson WK, Sponer J. J Chem Theory Comput. 2012;8:335–347. PubMed PMC

Svozil D, Kalina J, Omelka M, Schneider B. Nucleic Acids Res. 2008;36:3690–3706. PubMed PMC

Sponer J, Spackova N. Methods. 2007;43:278–290. PubMed PMC

Phillips K, Dauter Z, Murchie AIH, Lilley DMJ, Luisi B. J Mol Biol. 1997;273:171–182. PubMed

Deng JP, Xiong Y, Sundaralingam M. Proc Natl Acad Sci USA. 2001;98:13665–13670. PubMed PMC

Tereshko V, Wilds CJ, Minasov G, Prakash TP, Maier MA, Howard A, Wawrzak Z, Manoharan M, Egli M. Nucleic Acids Res. 2001;29:1208–1215. PubMed PMC

Case DA, TAD, Cheatham TE, III, Simmerling CL, Wang J, Duke RE, Luo R, Crowley M, RCW, Zhang W, Merz KM, Wang B, Hayik S, Roitberg A, Seabra G, Kolossváry I, KFW, Paesani F, Vanicek J, Wu X, Brozell SR, Steinbrecher T, Gohlke H, Yang L, CT, Mongan J, Hornak V, Cui G, Mathews DH, Seetin MG, Sagui C, Babin V, Kollman aPA. Amber. Vol. 10. University of California; San Francisco: 2008.

Cheatham TE, Cieplak P, Kollman PA. J Biomol Struct Dyn. 1999;16:845–862. PubMed

Krishnan R, Binkley JS, Seeger R, Pople JA. J Chem Phys. 1980;72:650–654.

Clark T, Chandrasekhar J, Spitznagel GW, Schleyer PV. J Comput Chem. 1983;4:294–301.

Gill PMW, Johnson BG, Pople JA. J Chem Phys. 1992;96:7178–7179.

Frisch MJ, Pople JA, Binkley JS. J Chem Phys. 1984;80:3265–3269.

Klamt A, Schuurmann G. J Chem Soc, Perkin Trans. 1993;2:799–805.

Ahlrichs R, Bar M, Haser M, Horn H, Kolmel C. Chem Phys Lett. 1989;162:165–169.

Halkier A, Helgaker T, Jorgensen P, Klopper W, Koch H, Olsen J, Wilson AK. Chem Phys Lett. 1998;286:243–252.

Halkier A, Helgaker T, Jorgensen P, Klopper W, Olsen J. Chem Phys Lett. 1999;302:437–446.

Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Montgomery JA, Vreven T, Kudin KN, Burant JC, Millam JM, Iyengar SS, Tomasi J, Barone V, Mennucci B, Cossi M, Scalmani G, Rega N, Petersson GA, Nakatsuji H, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Klene M, Li X, Knox JE, Hratchian HP, Cross JB, Bakken V, Adamo C, Jaramillo J, Gomperts R, Stratmann RE, Yazyev O, Austin AJ, Cammi R, Pomelli C, Ochterski JW, Ayala PY, Morokuma K, Voth GA, Salvador P, Dannenberg JJ, Zakrzewski VG, Dapprich S, Daniels AD, Strain MC, Farkas O, Malick DK, Rabuck AD, Raghavachari K, Foresman JB, Ortiz JV, Cui Q, Baboul AG, Clifford S, Cioslowski J, Stefanov BB, Liu G, Liashenko A, Piskorz P, Komaromi I, Martin RL, Fox DJ, Keith T, Laham A, Peng CY, Nanayakkara A, Challacombe M, Gill PMW, Johnson B, Chen W, Wong MW, Gonzalez C, Pople JA. Gaussian 03, Revision C.02. Gaussian, Inc; Wallingford, CT: 2004.

Jorgensen WL, Chandrasekhar J, Madura JD, Impey RW, Klein ML. J Chem Phys. 1983;79:926–935.

Jorgensen WL. J Am Chem Soc. 1981;103:335–340.

Berendsen HJC, Grigera JR, Straatsma TP. J Phys Chem. 1987;91:6269–6271.

Mahoney MW, Jorgensen WL. J Chem Phys. 2000;112:8910–8922.

Aqvist J. J Phys Chem. 1990;94:8021–8024.

Dang LX, Kollman PA. J Phys Chem. 1995;99:55–58.

Smith DE, Dang LX. J Chem Phys. 1994;100:3757–3766.

Sklenovsky P, Florova P, Banas P, Reblova K, Lankas F, Otyepka M, Sponer J. J Chem Theory Comput. 2011;7:2963–2980. PubMed

Darden T, York D, Pedersen L. J Chem Phys. 1993;98:10089–10092.

Essmann U, Perera L, Berkowitz ML, Darden T, Lee H, Pedersen LG. J Chem Phys. 1995;103:8577–8593.

Berendsen HJC, Postma JPM, Vangunsteren WF, Dinola A, Haak JR. J Chem Phys. 1984;81:3684–3690.

Reblova K, Fadrna E, Sarzynska J, Kulinski T, Kulhanek P, Ennifar E, Koca J, Sponer J. Biophys J. 2007;93:3932–3949. PubMed PMC

Besseova I, Otyepka M, Reblova K, Sponer J. Phys Chem Chem Phys. 2009;11:10701–10711. PubMed

Humphrey W, Dalke A, Schulten K. J Mol Graph. 1996;14:33. PubMed

Altona C, Sundaralingam M. J Am Chem Soc. 1972;94:8205. PubMed

Haider S, Parkinson GN, Neidle S. J Mol Biol. 2002;320:189–200. PubMed

Horvath MP, Schultz SC. J Mol Biol. 2001;310:367–377. PubMed

Hazel P, Parkinson GN, Neidle S. J Am Chem Soc. 2006;128:5480–5487. PubMed

Campbell NH, Smith DL, Reszka AP, Neidle S, O’Hagan D. Org Biomol Chem. 2011;9:1328–1331. PubMed

Gill ML, Strobel SA, Loria JP. Nucleic Acids Res. 2006;34:4506–4514. PubMed PMC

Brzezinski K, Brzuszkiewicz A, Dauter M, Kubicki M, Jaskolski M, Dauter Z. Nucleic Acids Res. 2011;39:6238–6248. PubMed PMC

Dauter Z, Adamiak DA. Acta Crystallogr, Sect D: Biol Crystallogr. 2001;57:990–995. PubMed

Gessner RV, Frederick CA, Quigley GJ, Rich A, Wang AHJ. J Biol Chem. 1989;264:7921–7935. PubMed

Lee J, Kim YG, Kim KK, Seok C. J Phys Chem B. 2010;114:9872–9881. PubMed

Wang AHJ, Quigley GJ, Kolpak FJ, Vandermarel G, Vanboom JH, Rich A. Science. 1981;211:171–176. PubMed

Dickerson RE, Grzeskowiak K, Grzeskowiak M, Kopka ML, Larsen T, Lipanov A, Prive GG, Quintana J, Schultze P, Yanagi K, Yuan H, Yoon HC. Nucleosides, Nucleotides Nucleic Acids. 1991;10:3–24.

Sponer J, Kypr J. J Biomol Struct Dyn. 1993;11:277–292. PubMed

Dickerson RE, Goodsell DS, Neidle S. Proc Natl Acad Sci USA. 1994;91:3579–3583. PubMed PMC

Kielkopf CL, Ding S, Kuhn P, Rees DC. J Mol Biol. 2000;296:787–801. PubMed

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