Probing Diffusive and Energetic Aspects of Ribosome Function

Abstract

As the scale of modern computers continues to grow, it is becoming possible to use theoretical models to quantitatively study of the energy landscapes and diffusive aspects of large-scale conformational transitions in molecular machines. One of the largest biomolecular assemblies, for which we have atomic-resolution structural data, is the ribosome. To elucidate the relationship between the structural, energetic, diffusive and kinetic aspects of large-scale collective dynamics, we use molecular dynamics simulations with simplified energetics models (40,000-150,000 atoms per simulation), in addition to explicit-solvent simulations of complete ribosomes (2-3 million atoms). Our simplified models are revealing coordinate-dependent diffusive properties of large-scale rearrangements in the ribosome, and are suggesting which coordinates most accurately capture the underlying barriers. Complementing this description, multi-hundred nanosecond explicit-solvent simulations suggest that the energy landscape of tRNA accommodation is relatively smooth. For translocation, we used a long (> 1 microsecond) explicit-solvent simulation to measure diffusion coefficients along collective (hundreds of residues) rearrangements in the ribosomal subunits. Grounded in energy landscape theory, as developed in the context of protein folding, these calculations provide a theoretical framework for understanding the relationship between experimental kinetics, single-molecule measurements, and theoretical predictions of the free-energy barriers that govern ribosome function.