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Chapter 6 : Effects of Pseudouridylation on tRNA Hydration and Dynamics: a Theoretical Approach

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Abstract:

This chapter focuses on the structural implications resulting from the occurrence of this residue in tRNA and also presents an overview of the tRNA pseudouridylation sites. The principle of molecular dynamics (MD) resides in the numerical integration of the Newtonian equations of motion. The potential energy function contains several terms that account for covalent bond stretching, bond angle bending, harmonic dihedral bending, and nonbonded interactions including van der Waals and Coulombic terms. The residence time of this water molecule, which is consistently observed in several MD simulations, was estimated to be significantly longer than 500 ps. This water molecule forms an important structural link between the nucleotide backbone and the modified base and, thus, reduces the conformational mobility of the RNA close to the pseudouridylation site. Summarizing the preceding information suggests strongly that the main function of pseudouridylation close to the anticodon is to stabilize the structure of the loop by reducing its intrinsic dynamics, likely to avoid codon misreading. Pseudouridines are also important in ribosomal RNA and small nuclear RNA. It would not be surprising that in most structural contexts pseudouridines would stabilize rRNA and snRNA in a similar manner as in tRNA. In snRNA, the occurrence of pseudouridines in single-stranded regions may be required to improve their recognition features. Recent MD studies on the conformational behavior of 2'-OH groups in tRNA may be considered as a first approach toward the investigation of the roles of 2'-O-methyl groups.

Citation: Auffinger P, Westhof E. 1998. Effects of Pseudouridylation on tRNA Hydration and Dynamics: a Theoretical Approach, p 103-112. In Grosjean H, Benne R (ed), Modification and Editing of RNA. ASM Press, Washington, DC. doi: 10.1128/9781555818296.ch6

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Figures

Image of Figure 1
Figure 1

Secondary structure of the yeast tRNA anticodon hairpin.

Citation: Auffinger P, Westhof E. 1998. Effects of Pseudouridylation on tRNA Hydration and Dynamics: a Theoretical Approach, p 103-112. In Grosjean H, Benne R (ed), Modification and Editing of RNA. ASM Press, Washington, DC. doi: 10.1128/9781555818296.ch6
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Image of Figure 2
Figure 2

Locations and frequencies of tRNA pseudouridylation sites extracted from the tRNA database containing 546 tRNA sequences ( ). Sites for which more than 10 modifications have been counted are surrounded by a bold circle. The letters A, Β and Ε refer to the three kingdoms (A, archaea [59 sequences]; B, eubacteria [133 sequences], and E, eukaryotes [212 sequences], while Ο includes the remaining 142 mitochondrial, chloroplastic and viroid tRNA sequences. The black square marks modifications occurring in all four (Α, Β, Ε and O) subdomains; the (not Α), (not B) and ε (not E) symbols mark modifications occurring respectively in the (Β, Ε, Ο), (A, E, O), and (A, B, O) subdomains. For the tRNA numbering, see and Appendix 5. The asterisk indicates that the sequence of minor tRNA containing the rare ΨΑΨanticodon ( ) has been added to the present compilation.

Citation: Auffinger P, Westhof E. 1998. Effects of Pseudouridylation on tRNA Hydration and Dynamics: a Theoretical Approach, p 103-112. In Grosjean H, Benne R (ed), Modification and Editing of RNA. ASM Press, Washington, DC. doi: 10.1128/9781555818296.ch6
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Image of Figure 3
Figure 3

(Top) Snapshot extracted from a 500-ps MD simulation of the solvated yeast tRNA anticodon hairpin. This snapshot shows the water molecule linking the base of Ψ to its nucleotide backbone through a N-H...O and two O-H...O hydrogen bonds (O = pro-R). This water molecule is stable for at least 500 ps and contributes to reduce the mobility of base 32 ( ). This reduced conformational mobility results in the stabilization of the single bifurcated (Ψ)O...Ν(C) interaction specific of the 32-38 "pseudo-base pair". (Bottom) Typical time course of the (Ψ)O...Ν(C) distance extracted from a 500-ps MD simulation of the solvated yeast tRNAAsp anticodon hairpin ( ).

Citation: Auffinger P, Westhof E. 1998. Effects of Pseudouridylation on tRNA Hydration and Dynamics: a Theoretical Approach, p 103-112. In Grosjean H, Benne R (ed), Modification and Editing of RNA. ASM Press, Washington, DC. doi: 10.1128/9781555818296.ch6
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Image of Figure 4
Figure 4

Substitution of a pyrimidine at position 35 of the anticodon loop by a pseudouridine. (Left) The occurrence of a (U)C-H...O,(U) hydrogen bond is inferred from the refined crystal structure of yeast tRNAAsp (Westhof et al., 1985). This interaction is analogous to the (A)N...H-O,(U) hydrogen bond found in the crystal structure of tRNAPhe ( ). This C-H...O interaction displays a stable dynamical behavior in several MD simulations of the tRNAAsp anticodon hairpin ( ). (Right) Substitution of a pyrimidine at position 35 by a pseudouridine increases the strength of the interaction established between base 35 and the ribose hydroxyl group of base 33, since a C-H...O contact is replaced by an N-H...O bond

Citation: Auffinger P, Westhof E. 1998. Effects of Pseudouridylation on tRNA Hydration and Dynamics: a Theoretical Approach, p 103-112. In Grosjean H, Benne R (ed), Modification and Editing of RNA. ASM Press, Washington, DC. doi: 10.1128/9781555818296.ch6
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Figure 5

Substitution for a pyrimidine at position 36 of the anticodon loop by a pseudouridine. (Left) A (C)C-H...O(U) interaction is present in the crystal structure of yeast tRNAAsp ( ). This interaction is maintained in several 500-ps MD simulations of the anticodon hairpin ( ). Additionally, U, is stabilized by the strong (U)N-H...O(C) internucleotide hydrogen bond and the weaker (U)C-H...O′ intranucleotide C-H...O interaction. The base of C is similarly linked to its backbone through a C Η...O′ hydrogen bond. U is thus linked to C through an array of strong N-H...O and weaker C-H...O hydrogen bonds. (Right) A replacement of a pyrimidine at position 36 by a pseudouridine would not perturb the array of existing hydrogen bonds at positions 33 and 36. Instead, it results in a strengthening of the interaction established between the two bases through the replacement of the C-H...O interaction by an N-H...O hydrogen bond.

Citation: Auffinger P, Westhof E. 1998. Effects of Pseudouridylation on tRNA Hydration and Dynamics: a Theoretical Approach, p 103-112. In Grosjean H, Benne R (ed), Modification and Editing of RNA. ASM Press, Washington, DC. doi: 10.1128/9781555818296.ch6
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