Allosteric Signal Transduction in the Ribosome: A Molecular Dynamics Study
The ribosome is a molecular machine that synthesizes cell proteins in the course of mRNA translation. At the each step of polypeptide chain synthesis, the ribosome ligands, tRNAs and several protein factors, bind and leave the ribosome in a strictly coordinated way. Also, it is known that the coordination of these steps is based on interrelated conformational rearrangements of components of the ribosome. It is generally accepted that coordination of the ordered sequence of events in the ribosomal working cycle is accomplished by signal exchange between functional centers of the ribosome. Since distances between these centers are rather large, it has been suggested that signal transduction in the ribosome might be performed allosterically. In this work, we attempt to explain how the allosteric signal can be transferred from one of the so-called sensory centers of the ribosomal nascent peptide exit tunnel (NPET) to the peptidyl transferase center (PTC) of the E. coli ribosome is made. To address this question, we use molecular dynamics modeling of the putative signal-transmission pathway that includes universally conserved 23S rRNA residues A2058, A2059, m <sup>2</sup>A2503, G2061, A2062, and C2063. We found that this rRNA segment constitutes a dynamic ensemble of interrelated conformational states. Moreover, we observed that these conformational changes could occur as a cascade. We suggest that restructuring of the A2058-C2063 region of NPET leads to reversible stalling of PTC due to stacking interactions of the functionally important U2585 residue with C2063. The possible role of the observed conformational changes in the regulation of the work of the ribosome is discussed.