Investigation of Allosteric Effect of 2,8-Dimethylation of A2503 in E. coli 23S rRNA by Molecular-Dynamics Simulations
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Investigation of Allosteric Effect of 2,8Dimethylation of A2503 in E. coli 23S rRNA by MolecularDynamics Simulations T. M. Makarova1,a* and G. I. Makarov1 1
South Ural State University, 454080 Chelyabinsk, Russia a email: [email protected] Received June 15, 2020 Revised October 1, 2020 Accepted October 2, 2020
Abstract—Ribosome is a molecular machine that synthesizes all cellular proteins. It also is a target of about half of the clin ically used antibiotics. Adaptive chemical modification of ribosomal RNAs residues is one of the ways to provide resistance to certain antibiotics. A curious example of such modification is 2,8dimethylation of A2503 in 23S rRNA, which induces resistance to phenols, linkosamides, oxazolidinones, pleuromutilins, and certain macrolides. In this article the effect of 2,8 dimethylation of A2503 on conformation and mobility of RNA residues of the 70S E. coli ribosome was investigated employ ing molecular dynamics simulations method. Significant alterations were detected both in the immediate environment of the 2503 23S rRNA residue and in the nucleotides located deeper in the nascent peptide exit tunnel (NPET), which are known to be involved in signal transmission from the antibiotics bound in the NPET to the peptidyl transferase center. These alterations shift the ribosome towards the A/A, P/Pstate from the conformationally different state – P/P, E/E one in our case. The obtained results allow us to conclude that the effect of m2m8A2503 modification involves additional stabilization of the A/A, P/Pstate favoring the peptidyl transferase reaction (PTR) contrary to antibiotics that inhibit PTR. DOI: 10.1134/S0006297920110139 Keywords: ribosome, resistance, antibiotics, A2503, molecular dynamics
INTRODUCTION Ribosome is a large ribonucleoprotein complex that synthesizes all cellular proteins according to the program delivered by messenger RNA. Being one of the key ele ments of a living cell, this ancient molecular machine contains universally conserved structural elements built from ribosomal RNA (rRNA) that relatively rarely mutate under natural conditions [1]. This circumstance along with the existence of multiple copies of ribosomal RNA gene in genomes of living organisms made the ribo some a logical target for a variety of antibiotics [2]. Approximately half of the antibiotics used today in the clinical practice are inhibitors of protein synthesis on the ribosome. Nevertheless, the number of pathogenic microorganisms resistant to ribosomal antibiotics is grow ing every year [2, 3]. The mechanism of bacterial ribosome resistance to antibiotics is usually realized via chemical modifications Abbreviations: MD, molecular dynamics; NPET, nascent pep tide exit tunnel; PTC, peptidyl transferase center. * To whom correspondence should be addressed.
of rRNA residues, predominantly concentrated in the ribosome functional centers [4], and these modifications comprise an additional nonconstitutional methylation of one or another rRNA residue [5]. An example of this is methylation of
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