Molecular dynamics simulations of human tRNA UUU : the role of modified bases in mRNA recognition

Accuracy in translation of the genetic code into proteins depends upon correct tRNA–mRNA recognition in the context of the ribosome. In human tRNA UUU three modified bases are present in the anticodon stem–loop—2-methylthio-N6-threonylcarbamoyladenosine at position 37 (mstA37), 5-methoxycarbonylmethyl-2-thiouridine at position 34 (mcmsU34) and pseudouridine (c) at position 39—two of which, mstA37 and mcmsU34, are required to achieve wild-type binding activity of wild-type human tRNA 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 stairstepped conformation. The mst modification at position 37 is required for maintenance of this structure and reduces solvent accessibility of U36. MstA37 generally hydrogen bonds across the loop and may prevent U36 from rotating into solution. A water molecule does coordinate to c39 most of the simulation time but weakly, as most of the residence lifetimes are ,40 ps.