Albany 2015:Book of Abstracts
June 9-13 2015
©Adenine Press (2012)
Simulating mRNA-tRNA Translocation through the Ribosome
Biomolecular simulations have been instrumental in elucidating the relationship among structure, function, and dynamics. Owing to rapid increases in computing capacity, and remarkable advances in structure determination by X-ray crystallography and cryoelectron microscopy (cryo-EM), molecular dynamics (MD) simulations may now be used to study large molecular machines, such as the ribosome. In the cell, messenger RNA (mRNA) sequences are translated into proteins by the joint action of the ribosome and transfer RNA (tRNA) molecules. During the elongation cycle of translation, tRNA molecules move (along with the mRNA) between binding sites in the ribosome, to allow the next mRNA codon to be decoded. In this process, known as translocation, tRNA movement (~20-50Å) proceeds via intermediate conformations, and involves large-scale rotations in the ribosomal subunits. To illuminate the physical relationship between these rotations and the movement of the tRNAs, we apply MD simulations using a simplified energetics model that elucidates the role of sterics and molecular flexibility. For the ribosome, we constructed forcefields for which each "classical" ribosome configuration is a potential energy minimum. Using these models, we obtained 250 simulated translocation events, and systematically partitioned factors that determine function and dynamics. We identify robust features of the process, and find that detailed steric interactions are a dominant contributor to the dynamics. Our results provide a conceptual energy landscape framework for understanding translocation dynamics, and suggest strategies to experimentally modulate the physical-chemical features that govern ribosome function.