35 The energy landscapes of ribosome function

Abstract

The vast information available about ribosome structure and dynamics makes it the ideal system for systematically investigating the physical–chemical properties that lead to biological function. To provide a comprehensive framework for understanding the relationship between the structural, energetic, diffusive, and kinetic aspects of large-scale collective dynamics, we use explicit-solvent simulations of complete ribosomes (2–3 million atoms), in addition to molecular models that employ simplified descriptions of the energetics (40,000–150,000 atoms per simulation). From multi-hundred nanosecond explicit-solvent simulations, we have established a quantitative relationship between tRNA accommodation and its associated free-energy barriers. For translocation, we have performed a 1.4-microsecond explicit-solvent simulation, from which we identified specific coordinate-spaces that capture the diffusive aspects of large-scale ‘ratcheting’ and ‘swivel’ rearrangements, thus providing physics-based coordinates for describing the free-energy landscape of translocation. To complement explicit-solvent calculations, we use all-atom simulations that employ simplified energetic models, with which we partition the contribution of molecular flexibility and energetics during accommodation and translocation. With these simpler models, the role of electrostatic screening and the responsiveness of the energy landscape to external perturbations are now being elucidated, which may aid in the design of novel antibiotics. Building on the principles of energy landscape theory, these calculations provide a comprehensive theoretical foundation with which experimental kinetics, single-molecule measurements, structural/mutational data, and theoretical calculations may be consistently interpreted and analyzed.