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Molecular dynamics simulations of human tRNA Lys,3 UUU: the role of modified bases in mRNA recognition.

McCrate NE, Varner ME, Kim KI, Nagan MC - Nucleic Acids Res. (2006)

Bottom Line: Guenther, A.The ms2t6 modification at position 37 is required for maintenance of this structure and reduces solvent accessibility of U36.A water molecule does coordinate to psi39 most of the simulation time but weakly, as most of the residence lifetimes are <40 ps.

View Article: PubMed Central - PubMed

Affiliation: Division of Science, Truman State University, 100 East Normal, Kirksville MO 63501, USA.

ABSTRACT
Accuracy in translation of the genetic code into proteins depends upon correct tRNA-mRNA recognition in the context of the ribosome. In human tRNA(Lys,3)UUU three modified bases are present in the anticodon stem-loop--2-methylthio-N6-threonylcarbamoyladenosine at position 37 (ms2t6A37), 5-methoxycarbonylmethyl-2-thiouridine at position 34 (mcm5s2U34) and pseudouridine (psi) at position 39--two of which, ms2t6A37 and mcm5s2U34, are required to achieve wild-type binding activity of wild-type human tRNA(Lys,3)UUU [C. Yarian, M. Marszalek, E. Sochacka, A. Malkiewicz, R. Guenther, A. Miskiewicz and P. F. Agris (2000) Biochemistry, 39, 13390-13395]. Molecular dynamics simulations of nine tRNA anticodon stem-loops with different combinations of nonstandard bases were performed. The wild-type simulation exhibited a canonical anticodon stair-stepped conformation. The ms2t6 modification at position 37 is required for maintenance of this structure and reduces solvent accessibility of U36. Ms2t6A37 generally hydrogen bonds across the loop and may prevent U36 from rotating into solution. A water molecule does coordinate to psi39 most of the simulation time but weakly, as most of the residence lifetimes are <40 ps.

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Conformations of ms2t6A. (A) with an ureido ring (B) without an ureido ring as calculated at the MPW1K/6-31+G (d,p) level of theory.
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fig4: Conformations of ms2t6A. (A) with an ureido ring (B) without an ureido ring as calculated at the MPW1K/6-31+G (d,p) level of theory.

Mentions: The bulky ms2t6 modification containing hydrogen bond donors and acceptors may act sterically to restrict A37 movement while discouraging the displacement of U36 through weak stacking interactions and stabilizing the position of A37 through hydrogen bond contacts across the loop. In the wild-type 2 simulation, where the bulk of the t6A substituent's hydrogen bond donors and acceptors are solvent exposed, U36 exhibits markedly increased conformational freedom. This behavior suggests a delicate balance of forces, of which cross-strand hydrogen bonding is a portion, preventing the displacement of U36 (Figure 4).


Molecular dynamics simulations of human tRNA Lys,3 UUU: the role of modified bases in mRNA recognition.

McCrate NE, Varner ME, Kim KI, Nagan MC - Nucleic Acids Res. (2006)

Conformations of ms2t6A. (A) with an ureido ring (B) without an ureido ring as calculated at the MPW1K/6-31+G (d,p) level of theory.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC1636460&req=5

fig4: Conformations of ms2t6A. (A) with an ureido ring (B) without an ureido ring as calculated at the MPW1K/6-31+G (d,p) level of theory.
Mentions: The bulky ms2t6 modification containing hydrogen bond donors and acceptors may act sterically to restrict A37 movement while discouraging the displacement of U36 through weak stacking interactions and stabilizing the position of A37 through hydrogen bond contacts across the loop. In the wild-type 2 simulation, where the bulk of the t6A substituent's hydrogen bond donors and acceptors are solvent exposed, U36 exhibits markedly increased conformational freedom. This behavior suggests a delicate balance of forces, of which cross-strand hydrogen bonding is a portion, preventing the displacement of U36 (Figure 4).

Bottom Line: Guenther, A.The ms2t6 modification at position 37 is required for maintenance of this structure and reduces solvent accessibility of U36.A water molecule does coordinate to psi39 most of the simulation time but weakly, as most of the residence lifetimes are <40 ps.

View Article: PubMed Central - PubMed

Affiliation: Division of Science, Truman State University, 100 East Normal, Kirksville MO 63501, USA.

ABSTRACT
Accuracy in translation of the genetic code into proteins depends upon correct tRNA-mRNA recognition in the context of the ribosome. In human tRNA(Lys,3)UUU three modified bases are present in the anticodon stem-loop--2-methylthio-N6-threonylcarbamoyladenosine at position 37 (ms2t6A37), 5-methoxycarbonylmethyl-2-thiouridine at position 34 (mcm5s2U34) and pseudouridine (psi) at position 39--two of which, ms2t6A37 and mcm5s2U34, are required to achieve wild-type binding activity of wild-type human tRNA(Lys,3)UUU [C. Yarian, M. Marszalek, E. Sochacka, A. Malkiewicz, R. Guenther, A. Miskiewicz and P. F. Agris (2000) Biochemistry, 39, 13390-13395]. Molecular dynamics simulations of nine tRNA anticodon stem-loops with different combinations of nonstandard bases were performed. The wild-type simulation exhibited a canonical anticodon stair-stepped conformation. The ms2t6 modification at position 37 is required for maintenance of this structure and reduces solvent accessibility of U36. Ms2t6A37 generally hydrogen bonds across the loop and may prevent U36 from rotating into solution. A water molecule does coordinate to psi39 most of the simulation time but weakly, as most of the residence lifetimes are <40 ps.

Show MeSH