Non-bulk-like solvent behavior in the ribosome exit tunnel.

Del Lucent,Vijay S Pande,Christopher D Snow,Colin Echeverría Aitken

doi:10.1371/journal.pcbi.1000963

Abstract

As nascent proteins are synthesized by the ribosome, they depart via an exit tunnel running through the center of the large subunit. The exit tunnel likely plays an important part in various aspects of translation. Although water plays a key role in many bio-molecular processes, the nature of water confined to the exit tunnel has remained unknown. Furthermore, solvent in biological cavities has traditionally been characterized as either a continuous dielectric fluid, or a discrete tightly bound molecule. Using atomistic molecular dynamics simulations, we predict that the thermodynamic and kinetic properties of water confined within the ribosome exit tunnel are quite different from this simple two-state model. We find that the tunnel creates a complex microenvironment for the solvent resulting in perturbed rotational dynamics and heterogenous dielectric behavior. This gives rise to a very rugged solvation landscape and significantly retarded solvent diffusion. We discuss how this non-bulk-like solvent is likely to affect important biophysical processes such as sequence dependent stalling, co-translational folding, and antibiotic binding. We conclude with a discussion of the general applicability of these results to other biological cavities.

Highlights

The first microenvironment a protein experiences is that of the ribosome exit tunnel, the long cavity in the large ribosomal subunit through which the nascent peptide emerges during translation
Using molecular dynamics simulations we report on the thermodynamic and kinetic properties of water confined to the ribosome exit tunnel
We modeled the ribosome exit tunnel in all-atom detail for the ribosome and solvent

Summary

Introduction

The first microenvironment a protein experiences is that of the ribosome exit tunnel, the long cavity in the large ribosomal subunit through which the nascent peptide emerges during translation. A number of protein sequences have been shown to stall translation, presumably via specific interactions with the exit tunnel. Most notable among these are the tnaC and SecM sequences [4]. Lu et al have shown by site-specific chemical modification of particular nascent peptide sequences that the electrostatic potential in the tunnel is predominantly negative and quite heterogeneous [7]. Nascent peptide sequences with stretches of positive amino acids have been shown to transiently stall translation in accordance with the known electrostatic characterization of the tunnel [8]. The SecM sequence is compacted while in the exit tunnel, and this compaction is necessary for stalling [12]

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Conclusion