Molecular simulations of the ribosome and associated translation factors

Abstract

The ribosome is a macromolecular complex which is responsible for protein synthesis in all living cells according to their transcribed genetic information. Using X-ray crystallography and, more recently, cryo-electron microscopy (cryo-EM), the structure of the ribosome was resolved at atomic resolution in many functional and conformational states. Molecular dynamics simulations have added information on dynamics and energetics to the available structural information, thereby have bridged the gap to the kinetics obtained from single-molecule and bulk experiments. Here, we review recent computational studies that brought notable insights into ribosomal structure and function.

Structural Heterogeneities of the Ribosome: New Frontiers and Opportunities for Cryo-EM

“…Yet, detailed 3D structures can serve as an important basis or complement for more direct studies of the underlying kinetics. Coarse-grained and atomistic molecular dynamics simulations take 3D structures as an input to model the thermodynamic and kinetic properties of the ribosome [ 86 , 87 ]. On the experimental side, understanding the 3D structure has been useful to guide and interpret single molecule fluorescence imaging experiments which offer time series data of the ribosome [ 78 , 88 ].…”

tRNA dissociation from EF-Tu after GTP hydrolysis and Pirelease: primary steps and antibiotic inhibition

“…Due to the relatively short timescales that can currently be covered with unrestrained explicit-solvent all-atom MD simulation [53], the subsequent steps of full EF-Tu dissociation from the ribosome and the tRNA are not observed in our simulations. Based on biased MD simulations, Lai et al proposed a pathway from the closed GTP-bound conformation to the open GDP-bound conformation which involves a separation of D1 from D2 and D3, followed by a rotation of D1 and a subsequent rejoining of D1 with D2 and D3 in the GTP-bound conformation [54].…”

Assembly of heteropolymers via a network of reaction coordinates

“…In principle, one could infer a reaction coordinate description from molecular dynamics simulation of replicating enzymes [23]. Projection methods can be used for such dimensional reduction [25?…”

“…For highly irreversible processes, the error η should mainly depend on the activation energy difference δ r − δ r , see Eq. (23). We also expect that the reaction speed should increase for more irreversible processes.…”

“…A radically opposite approach is to simulate heteropolymer assembly using molecular dynamics [23]. From the molecular dynamics, one can project the numerous degrees of freedom into a 1-Dimensional collective variable called reaction coordinate [24].…”