Structural studies of ribosome-SelB complexes and ribosome nascent chain folding intermediates by cryo-EM and molecular dynamics simulations
Final Report Abstract
During the course of this project, we performed several studies where we combined high-resolution cryo-EM studies with molecular dynamics simulations. With the recent developments in cryo-EM it becomes now possible to determine several distinct states of a macromolecular complex from one given dataset. This allows to determine several intermediates of a process by solving the structure of those snapshots which can subsequently be ordered in a functional meaningful manner if additional biochemical and/or functional data allows this. However, all cryo-EM structures are snapshots only and will never provide detailed quantitative about the energetics that could reveal the molecular details of energy barriers between those states and for example how a large complex like the ribosome maintains its interaction energies even during dramatic conformational rearrangements. The possibilities offered by state-of-the art cryo-EM provides a perfect basis for highly complementary work with molecular dynamics simulations that, in contrast to cryo-EM can provide quantitative information about molecular details of energy barriers and driving forces of certain conformational rearrangements in large complexes. This combination of cryo-EM and MD simulations in studies of the dynamic behavior of large macromolecules is unique to understand how such molecular machines work by considering their dynamic aspects at an unprecedented level of detail. Our results indeed provide fundamental new insights in how ribosomes work in the different steps of translation.
Publications
- Energy barriers and driving forces in tRNA translocation through the ribosome. Nature Struct. Mol. Biol. 20 (12), 1390-1396 (2013)
Bock LV, Blau C, Schröder GF, Davydov II, Fischer N, Stark H, Rodnina MV, Vaiana AC, Grubmüller H
(See online at https://doi.org/10.1038/nsmb.2690) - g_contacts: Fast contact search in bio-molecular ensemble data. Comput. Phys. Comm. 184 (12), 2856-2859 (2013)
Blau C, Grubmüller H
(See online at https://doi.org/10.1016/j.cpc.2013.07.018) - Dynamic contact network between ribosomal subunits enables rapid large-scale rotation during spontaneous translocation. Nucl. Acids Res. 43 (14), 6747– 6760 (2015)
Bock LV, Blau C, Vaiana AC, Grubmüller H
(See online at https://doi.org/10.1093/nar/gkv649) - A combined cryo-EM and molecular dynamics approach reveals the mechanism of ErmBL-mediated translation arrest. Nature Comm. 7, 12026 (2016)
Arenz S, Bock LV, Graf M, Innis CA, Beckmann R, Grubmüller H, Vaiana AC, Wilson DN
(See online at https://doi.org/10.1038/ncomms12026) - The pathway to GTPase activation of elongation factor SelB on the ribosome. Nature 540 (7631), 80-85 (2016)
Fischer N, Neumann P, Bock LV, Maracci C, Wang Z, Paleskava A, Konevega AL, Schröder GF, Grubmüller H, Ficner R, Rodnina MV, Stark H
(See online at https://doi.org/10.1038/nature20560) - Structural Basis for Polyproline-Mediated Ribosome Stalling and Rescue by the Translation Elongation Factor EF-P. Mol. Cell 68 (3), 515–527 (2017)
Huter P, Arenz S, Bock LV, Graf M, Frister JO, Heuer A, Peil L, Starosta AL, Wohlgemuth I, Peske F, Novacek J, Berninghausen O, Grubmüller H, Tenson T, Beckmann R, Rodnina MV, Vaiana AC, Wilson DN
(See online at https://doi.org/10.1016/j.molcel.2017.10.014) - Molecular simulations of the ribosome and associated translation factors. Curr. Opin. Struct. Biol. 49, 27–35 (2018)
Bock LV, Kolar MH, Grubmüller H
(See online at https://doi.org/10.1016/j.sbi.2017.11.003)
