The hairpin ribozyme is a prominent member of small ribozymes since it does not require metal ions to achieve catalysis. Guanine 8 (G8) and adenine 38 (A38) have been identified as key participants in self-cleavage and -ligation. We have carried out hybrid quantum-mechanical/molecular mechanical (QM/MM) calculations to evaluate the energy along several putative reaction pathways. The error of our DFT description of the QM region was tested and shown to be ~1 kcal/mol. We find that self-cleavage of the hairpin ribozyme may follow several competing microscopic reaction mechanisms, all with calculated activation barriers in good agreement with those from experiment (20-21 kcal/mol). The initial nucleophilic attack of the A-1(2'-OH) group on the scissile phosphate is predicted to be rate-limiting in all these mechanisms. An unprotonated G8(-) (together with A38H(+)) yields a feasible activation barrier (20.4 kcal/mol). Proton transfer to a nonbridging phosphate oxygen also leads to feasible reaction pathways. Finally, our calculations consider thio-substitutions of one or both nonbridging oxygens of the scissile phosphate and predict that they have only a negligible effect on the reaction barrier, as observed experimentally.

Regional Centre of Advanced Technologies and Materials Department of Physical Chemistry Faculty of Science Palacky University tr 17 listopadu 12 771 46 Olomouc Czech Republic

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Buzayan JM, Hampel A, Bruening G. Nucleic Acids Res. 1986;14:9729–9743. PubMed PMC

Buzayan JM, Feldstein PA, Segrelles C, Bruening G. Nucleic Acids Res. 1988;16:4009–4023. PubMed PMC

van Tol H, Buzayan JM, Feldstein PA, Eckstein F, Bruening G. Nucleic Acids Res. 1990;18:1971–1975. PubMed PMC

Fedor MJ. Annu. Rev. Biophys. 2009;38:271–299. PubMed

Lilley DM. Trends Biochem. Sci. 2003;28:495–501. PubMed

Fedor MJ. J. Mol. Biol. 2000;297:269–291. PubMed

Walter NG, Burke JM. Curr. Opin. Chem. Biol. 1998;2:24–30. PubMed

Cochrane JC, Strobel SA. Acc. Chem. Res. 2008;41:1027–1035. PubMed

Pinard R, Hampel KJ, Heckman JE, Lambert D, Chan PA, Major F, Burke JM. EMBO J. 2001;20:6434–6442. PubMed PMC

Kuzmin YI, Da Costa CP, Fedor MJ. J. Mol. Biol. 2004;340:233–251. PubMed

Rupert PB, Ferre-D'Amare AR. Nature. 2001;410:780–786. PubMed

Rupert PB, Massey AP, Sigurdsson ST, Ferre-D'Amare AR. Science. 2002;298:1421–1424. PubMed

Salter J, Krucinska J, Alam S, Grum-Tokars V, Wedekind JE. Biochemistry. 2006;45:686–700. PubMed PMC

Lebruska LL, Kuzmine II, Fedor MJ. Chem. Biol. 2002;9:465–473. PubMed

Bevilacqua PC. Biochemistry. 2003;42:2259–2265. PubMed

Walter NG. Mol. Cell. 2007;28:923–929. PubMed PMC

Nam KH, Gao JL, York DM. J. Am. Chem. Soc. 2008;130:4680–4691. PubMed PMC

Nam K, Gao JL, York DM. RNA. 2008;14:1501–1507. PubMed PMC

Kuzmin YI, Da Costa CP, Cottrell JW, Fedor MJ. J. Mol. Biol. 2005;349:989–1010. PubMed

Guo M, Spitale RC, Volpini R, Krucinska J, Cristalli G, Carey PR, Wedekind JE. J. Am. Chem. Soc. 2009;131:12908–12909. PubMed PMC

Cottrell JW, Scott LG, Fedor MJ. J. Biol. Chem. 2011;286:17658–17664. PubMed PMC

Rhodes MM, Reblova K, Sponer J, Walter NG. Proc. Natl. Acad. Sci. U.S.A. 2006;103:13380–13385. PubMed PMC

Ditzler MA, Sponer J, Walter NG. RNA. 2009;15:560–575. PubMed PMC

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

Zirbel CL, Sponer JE, Sponer J, Stombaugh J, Leontis NB. Nucleic Acids Res. 2009;37:4898–4918. PubMed PMC

Liu L, Cottrell JW, Scott LG, Fedor MJ. Nat. Chem. Biol. 2009;5:351–357. PubMed PMC

Wilson TJ, Lilley DM. RNA. 2011;17:213–221. PubMed PMC

Cottrell JW, Kuzmin YI, Fedor MJ. J. Biol. Chem. 2007;282:13498–13507. PubMed

Suydam IT, Levandoski SD, Strobel SA. Biochemistry. 2010;49:3723–3732. PubMed PMC

Lide DR, editor. CRC Handbook of Chemistry and Physics. 83rd ed. CRC; Boca Raton: 2003.

Torelli AT, Krucinska J, Wedekind JE. RNA. 2007;13:1052–1070. PubMed PMC

Macelrevey C, Salter JD, Krucinska J, Wedekind JE. RNA. 2008;14:1600–1616. PubMed PMC

Torelli AT, Spitale RC, Krucinska J, Wedekind JE. Biochem. Biophys. Res. Commun. 2008;371:154–158. PubMed PMC

Spitale RC, Volpini R, Heller MG, Krucinska J, Cristalli G, Wedekind JE. J. Am. Chem. Soc. 2009;131:6093–6095. PubMed PMC

Warshel A, Levitt M. J. Mol. Biol. 1976;103:227–249. PubMed

Banas P, Jurecka P, Walter NG, Sponer J, Otyepka M. Methods. 2009;49:202–216. PubMed PMC

Otyepka M, Banas P, Magistrato A, Carloni P, Damborsky J. Proteins: Struct., Funct., Bioinf. 2008;70:707–717. PubMed

Banas P, Rulisek L, Hanosova V, Svozil D, Walter NG, Sponer J, Otyepka M. J. Phys. Chem. B. 2008;112:11177–11187. PubMed PMC

Warshel A, Sharma PK, Kato M, Xiang Y, Liu HB, Olsson MHM. Chem. Rev. 2006;106:3210–3235. PubMed

Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Scalmani G, Barone V, Mennucci B, Petersson GA, et al. Gaussian 09. Gaussian, Inc.; Wallingford CT: 2009.

Scalmani G, Frisch MJ. J. Chem. Phys. 2010;132:114110. PubMed

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.

Jurecka P, Hobza P. Chem Phys Lett. 2002;365:89–94.

Jurecka P, Hobza P. J. Am. Chem. Soc. 2003;125:15608–15613. PubMed

Svensson M, Humbel S, Froese RDJ, Matsubara T, Sieber S, Morokuma K. J. Phys. Chem. 1996;100:19357–19363.

Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Montgomery JA, Jr., Vreven T, Kudin KN, Burant JC, et al. Gaussian 03. Gaussian, Inc.; Pittsburgh: 2003.

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

Becke AD. Phys. Rev. A. 1988;38:3098–3100. PubMed

Lee CT, Yang WT, Parr RG. Phys. Rev. B. 1988;37:785–789. PubMed

Dunlap BI. J. Chem. Phys. 1983;78:3140–3142.

Dunlap BI. J. Mol. Struct. THEOCHEM. 2000;529:37–40.

Perreault DM, Anslyn EV. Angew. Chem., Int. Ed. Engl. 1997;36:432–450.

Lynch BJ, Fast PL, Harris M, Truhlar DG. J. Phys. Chem. A. 2000;104:4811–4815.

Lynch BJ, Truhlar DG. J. Phys. Chem. A. 2001;105:2936–2941.

Sponer J, Jurecka P, Marchan I, Luque FJ, Orozco M, Hobza P. Chem.-Eur. J. 2006;12:2854–2865. PubMed

Warshel A. Computer Modeling of Chemical Reactions in Enzymes and Solutions. John Wiley and Sons; New York: 1991.

Torres RA, Himo F, Bruice TC, Noodleman L, Lovell T. J. Am. Chem. Soc. 2003;125:9861–9867. PubMed

Liu Y, Gregersen BA, Lopez X, York DM. J. Phys. Chem. B. 2005;109:19987–20003. PubMed

Lopez X, Dejaegere A, Leclerc F, York DM, Karplus M. J. Phys. Chem. B. 2006;110:11525–11539. PubMed

Liu Y, Gregersen BA, Hengge A, York DM. Biochemistry. 2006;45:10043–10053. PubMed

Liu H, Robinet JJ, Ananvoranich S, Gauld JW. J. Phys. Chem. B. 2007;111:439–445. PubMed

Chval Z, Chvalova D, Leclerc F. J. Phys. Chem. B. 2011;115:10943–10956. PubMed

Boero M, Terakura K, Tateno M. J. Am. Chem. Soc. 2002;124:8949–8957. PubMed

Liu HN, Robinet JJ, Ananvoranich S, Gauld JW. J. Phys. Chem. B. 2007;111:439–445. PubMed

Tomasi J, Mennucci B, Cammi R. Chem. Rev. 2005;105:2999–3093. PubMed

Colominas C, Luque FJ, Orozco M. J. Am. Chem. Soc. 1996;118:6811–6821.

Zgarbova M, Jurecka P, Banas P, Otyepka M, Sponer JE, Leontis NB, Zirbel CL, Sponer J. J. Phys. Chem. A. 2011;115:11277–11292. PubMed

Young KJ, Gill F, Grasby JA. Nucleic Acids Res. 1997;25:3760–3766. PubMed PMC

Gao J, Ma S, Major DT, Nam K, Pu J, Truhlar DG. Chem. Rev. 2006;106:3188–3209. PubMed PMC

Ditzler MA, Otyepka M, Sponer J, Walter NG. Acc. Chem. Res. 2009 PubMed PMC

Hobza P, Sponer J. Chem. Rev. 1999;99:3247–3276. PubMed

Sponer J, Jurecka P, Hobza P. J. Am. Chem. Soc. 2004;126:10142–10151. PubMed

Morgado CA, Jurecka P, Svozil D, Hobza P, Sponer J. Phys. Chem. Chem. Phys. 2010;12:3522–3534. PubMed

Riley KE, Pitonak M, Jurecka P, Hobza P. Chem. Rev. 2010;110:5023–5063. PubMed

Lin H, Truhlar DG. Theor. Chem. Acc. 2007;117:185–199.

Nam K, Cui Q, Gao JL, York DM. J. Chem. Theory Comput. 2007;3:486–504. PubMed

Iyengar SS, Schlegel HB, Voth GA. J. Phys. Chem. A. 2003;107:7269–7277.

Voth GA, Rega N, Iyengar SS, Schlegel HB, Vreven T, Frisch MJ. J. Phys. Chem. B. 2004;108:4210–4220.

Bevilacqua PC, Brown TS, Nakano S, Yajima R. Biopolymers. 2004;73:90–109. PubMed

Banas P, Walter NG, Sponer J, Otyepka M. J. Phys. Chem. B. 2010;114:8701–8712. PubMed PMC

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