SecM leader peptide as an allosteric translation inhibitor: a molecular dynamics study.

The SecM leader peptide regulates translation of the SecA protein, being a part of the Sec translocase, that reversibly arrests the ribosome. In the present study the structure of the SecM complex with the E. coli A/A,P/P-ribosome was obtained by means of docking and molecular dynamics simulation methods. It has been established that binding of the SecM leader peptide in the nascent peptide exit tunnel leads to a turn of the aminoacylating proline residue away from the C-terminal SecM glycine residue, which is adverse to the peptidyltransferase reaction. Besides, the SecM binding leads to a disturbance of the A-tRNA contacts with the tip of the H38 helix of the 23S rRNA (the A-site finger, ASF) and ribosomal protein uL16. Allosteric interrelation between these events has been proved by a construction of networks of concerted changes in non-covalent interactions throughout the whole ribosome, whereupon the A1614 and A751 residues of the 23S rRNA in the exit tunnel that formed stacking interactions with the SecM residues during the MD simulations, were found to be the principal triggers, inducing crucial alterations in the A-tRNA binding. The allosteric signal from the SecM peptide to the ASF, according to our model, is transmitted through ribosomal protein uL22, and there is reason to believe that this sensor is used not only by the SecM leader peptide, but also by other peptides that cause translation arrest.