Molecular Dynamics Simulations Suggest a Non-Doublet Decoding Model of -1 Frameshifting by TRNA

Overview

Journal Biomolecules

Publisher MDPI

Specialties Biochemistry
Molecular Biology

Date 2019 Nov 23

PMID 31752208

Citations 8

Authors

Thomas Caulfield

Matt Coban

Alex Tek

Samuel Coulbourn Flores

Affiliations

Soon will be listed here.

Abstract

In-frame decoding in the ribosome occurs through canonical or wobble Watson-Crick pairing of three mRNA codon bases (a triplet) with a triplet of anticodon bases in tRNA. Departures from the triplet-triplet interaction can result in frameshifting, meaning downstream mRNA codons are then read in a different register. There are many mechanisms to induce frameshifting, and most are insufficiently understood. One previously proposed mechanism is doublet decoding, in which only codon bases 1 and 2 are read by anticodon bases 34 and 35, which would lead to -1 frameshifting. In E. coli, tRNA can induce -1 frameshifting at alanine (GCA) codons. The logic of the doublet decoding model is that the Ala codon's GC could pair with the tRNAs GC, leaving the third anticodon residue U36 making no interactions with mRNA. Under that model, a U36C mutation would still induce -1 frameshifting, but experiments refute this. We perform all-atom simulations of wild-type tRNA, as well as a U36C mutant. Our simulations revealed a hydrogen bond between U36 of the anticodon and G1 of the codon. The U36C mutant cannot make this interaction, as it lacks the hydrogen-bond-donating H3. The simulation thus suggests a novel, non-doublet decoding mechanism for -1 frameshifting by tRNA at Ala codons.

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References

Case D, Cheatham 3rd T, Darden T, Gohlke H, Luo R, Merz Jr K . The Amber biomolecular simulation programs. J Comput Chem. 2005; 26(16):1668-88. PMC: 1989667. DOI: 10.1002/jcc.20290. View

Weiss R, Dunn D, Atkins J, GESTELAND R . Slippery runs, shifty stops, backward steps, and forward hops: -2, -1, +1, +2, +5, and +6 ribosomal frameshifting. Cold Spring Harb Symp Quant Biol. 1987; 52:687-93. DOI: 10.1101/sqb.1987.052.01.078. View

Humphrey W, Dalke A, Schulten K . VMD: visual molecular dynamics. J Mol Graph. 1996; 14(1):33-8, 27-8. DOI: 10.1016/0263-7855(96)00018-5. View

Pettersen E, Goddard T, Huang C, Couch G, Greenblatt D, Meng E . UCSF Chimera--a visualization system for exploratory research and analysis. J Comput Chem. 2004; 25(13):1605-12. DOI: 10.1002/jcc.20084. View

Selmer M, Dunham C, Murphy 4th F, Weixlbaumer A, Petry S, Kelley A . Structure of the 70S ribosome complexed with mRNA and tRNA. Science. 2006; 313(5795):1935-42. DOI: 10.1126/science.1131127. View

Ivanov I, GESTELAND R, MATSUFUJI S, Atkins J . Programmed frameshifting in the synthesis of mammalian antizyme is +1 in mammals, predominantly +1 in fission yeast, but -2 in budding yeast. RNA. 1998; 4(10):1230-8. PMC: 1369695. DOI: 10.1017/s1355838298980864. View

Atkins J, GESTELAND R, Reid B, Anderson C . Normal tRNAs promote ribosomal frameshifting. Cell. 1979; 18(4):1119-31. DOI: 10.1016/0092-8674(79)90225-3. View

Meydan S, Klepacki D, Karthikeyan S, Margus T, Thomas P, Jones J . Programmed Ribosomal Frameshifting Generates a Copper Transporter and a Copper Chaperone from the Same Gene. Mol Cell. 2017; 65(2):207-219. PMC: 5270581. DOI: 10.1016/j.molcel.2016.12.008. View

Flores S, Sherman M, Bruns C, Eastman P, Altman R . Fast flexible modeling of RNA structure using internal coordinates. IEEE/ACM Trans Comput Biol Bioinform. 2011; 8(5):1247-57. PMC: 4428339. DOI: 10.1109/TCBB.2010.104. View

10.

Demeshkina N, Jenner L, Westhof E, Yusupov M, Yusupova G . A new understanding of the decoding principle on the ribosome. Nature. 2012; 484(7393):256-9. DOI: 10.1038/nature10913. View

11.

Atkins J, Loughran G, Bhatt P, Firth A, Baranov P . Ribosomal frameshifting and transcriptional slippage: From genetic steganography and cryptography to adventitious use. Nucleic Acids Res. 2016; 44(15):7007-78. PMC: 5009743. DOI: 10.1093/nar/gkw530. View

12.

Watts K, Dalal P, Tebben A, Cheney D, Shelley J . Macrocycle conformational sampling with MacroModel. J Chem Inf Model. 2014; 54(10):2680-96. DOI: 10.1021/ci5001696. View

13.

Clark M, Janicke M, Gottesbuhren U, Kleffmann T, Legge M, Poole E . Mammalian gene PEG10 expresses two reading frames by high efficiency -1 frameshifting in embryonic-associated tissues. J Biol Chem. 2007; 282(52):37359-69. DOI: 10.1074/jbc.M705676200. View

14.

Gaspar C, Jannatipour M, Dion P, Laganiere J, Sequeiros J, Brais B . CAG tract of MJD-1 may be prone to frameshifts causing polyalanine accumulation. Hum Mol Genet. 2000; 9(13):1957-66. DOI: 10.1093/hmg/9.13.1957. View

15.

Caulfield T, Fiesel F, Moussaud-Lamodiere E, Dourado D, Flores S, Springer W . Phosphorylation by PINK1 releases the UBL domain and initializes the conformational opening of the E3 ubiquitin ligase Parkin. PLoS Comput Biol. 2014; 10(11):e1003935. PMC: 4222639. DOI: 10.1371/journal.pcbi.1003935. View

16.

Flores S, Wan Y, Russell R, Altman R . Predicting RNA structure by multiple template homology modeling. Pac Symp Biocomput. 2009; :216-27. PMC: 2872935. DOI: 10.1142/9789814295291_0024. View

17.

Fagan C, Maehigashi T, Dunkle J, Miles S, Dunham C . Structural insights into translational recoding by frameshift suppressor tRNASufJ. RNA. 2014; 20(12):1944-54. PMC: 4238358. DOI: 10.1261/rna.046953.114. View

18.

Girstmair H, Saffert P, Rode S, Czech A, Holland G, Bannert N . Depletion of cognate charged transfer RNA causes translational frameshifting within the expanded CAG stretch in huntingtin. Cell Rep. 2013; 3(1):148-59. DOI: 10.1016/j.celrep.2012.12.019. View

19.

Caulfield T . Inter-ring rotation of apolipoprotein A-I protein monomers for the double-belt model using biased molecular dynamics. J Mol Graph Model. 2011; 29(8):1006-14. DOI: 10.1016/j.jmgm.2011.04.005. View

20.

Phillips J, Braun R, Wang W, Gumbart J, Tajkhorshid E, Villa E . Scalable molecular dynamics with NAMD. J Comput Chem. 2005; 26(16):1781-802. PMC: 2486339. DOI: 10.1002/jcc.20289. View