title: Simulating the pulling of stalled elongated peptide from the ribosome by the translocon.
abstract: The nature of the coupling between the stalling of the elongated nascent peptide chain in the ribosome and its insertion through the translocon is analyzed, focusing on the recently discovered biphasic force that overcomes the stalling barrier. The origin of this long-range coupling is explored by coarse-grained simulations that combine the translocon (TR) insertion profile and the effective chemical barrier for the extension of the nascent chain in the ribosome. Our simulation determined that the inserted H segment is unlikely to climb the TR barrier in parallel with the peptide synthesis chemical step and that the nascent chain should first overcome the chemical barriers and move into the ribosome-TR gap region before the insertion into the TR tunnel. Furthermore, the simulations indicate that the coupled TR-chemistry free energy profile accounts for the biphasic force. Apparently, although the overall elongation/insertion process can be depicted as a tug-of-war between the forces of the TR and the ribosome, it is actually a reflection of the combined free-energy landscape. Most importantly, the present study helps to relate the experimental observation of the biphasic force to crucial information about the elusive path and barriers of the TR insertion process.
authors.affiliation: Department of Chemistry, University of Southern California, Los Angeles, CA 90089-1062, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Rychkova
authors.forename: Shayantani
authors.initials: S
authors.lastname: Mukherjee
authors.forename: Ram Prasad
authors.initials: RP
authors.lastname: Bora
authors.forename: Arieh
authors.initials: A
authors.lastname: Warshel
mesh_terms: D000818:Animals; D003198:Computer Simulation; D004563:Electrochemistry; D004734:Energy Metabolism / Q000235:genetics; D006801:Humans; D008958:Models, Molecular; D010441:Peptide Chain Elongation, Translational / Q000502:physiology*; D014176:Protein Biosynthesis / Q000502:physiology*; D012270:Ribosomes / Q000737:chemistry* / Q000502:physiology*
keywords: Langevin dynamics; arrest peptide; coarse grained model; empirical valence bond; secM