A mechanistic view on rRNA - antibiotics binding

Abstract

The ribosome, which is the macromolecular machine for protein synthesis, is one of the most striking targets for the antimicrobial drugs. Antibiotics that block the protein synthesis in various ways in ribosome have different modes of action and binding sites in different microorganisms. The key interactions are mainly between ribosomal RNA (rRNA) and antibiotics. The interaction sites of these antibiotics with the rRNA, determined by biochemical, in vitro and in vivo cross-linking experiments and footprinting studies, are proved when the structures with antibiotics are discovered. We used the Gaussian Network Model (GNM) to predict antibiotic binding sites and their interactions with the ribosomal proteins. In the GNM, the structures are modeled as an elastic network, where the inter-residue interactions are harmonic. We have analyzed the vibrational modes of motion for 73 ribosome structures (64 bound, 9 unbound) from Deinococcus radiodurans, Escherichia coli, Haloarcula marismortui and Thermus thermophilus. We propose a mechanistic view for the antibiotics binding and to predict antibiotic binding sites and their interactions with the ribosomal proteins based on the dynamics of rRNA. The antibiotics binding sites are mainly located at the Peptidyl Transferase Center (PTC) and decoding center in 23S rRNA and 16S rRNA, respectively. The nucleotides showing high frequency fluctuations cluster in two regions and these two regions correspond to these two functional and known antibiotics binding sites. The nucleotides in the antibiotics binding sites and their adjacent nucleotides form a network of residues that are coupled in their high frequency fluctuations. This network may also lead to the allosteric interaction between the antibiotics binding sites and ribosomal proteins.