The aminoacyl-tRNA binding site (A-site) is located in helix 44 of small ribosomal subunit. The mobile adenines 1492 and 1493 (Escherichia coli numbering), forming the A-site bulge, act as a functional switch that ensures mRNA decoding accuracy. Structural data on the oligonucleotide models mimicking the ribosomal A-site with sequences corresponding to bacterial and human cytoplasmic sites confirm that this RNA motif forms also without the ribosome context. We performed all-atom molecular dynamics simulations of these crystallographic A-site models to compare their conformational properties. We found that the human A-site bulge is more internally flexible than the bacterial one and has different base pairing preferences, which result in the overall different shapes of these bulges and cation density distributions. Also, in the human A-site model we observed repetitive destacking of A1492, while A1493 was more stably paired than in the bacterial variant. Based on the dynamics of the A-sites we suggest why aminoglycoside antibiotics, which target the bacterial A-site, have lower binding affinities and anti-translational activities toward the human variant.

CEITEC Central European Institute of Technology Masaryk University Campus Bohunice Kamenice 5 625 00 Brno Czech Republic; Institute of Biophysics Academy of Sciences of the Czech Republic Královopolská 135 612 65 Brno Czech Republic

Centre of New Technologies University of Warsaw Banacha 2c 02 097 Warsaw Poland

Division of Biophysics Institute of Experimental Physics University of Warsaw Żwirki i Wigury 93 02 089 Warsaw Poland; Interdisciplinary Centre for Mathematical and Computational Modelling University of Warsaw Pawińskiego 5a 02 106 Warsaw Poland

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