Large-scale simulations of molecular machines: the ribosome

The ribosome plays a central role in all life forms and is responsible for protein synthesis. Here, the ribosome must read the genetic information and implement this information by producing the corresponding proteins. Approximately 50% of the antibiotic drugs used in US hospitals function by targeting the ribosome. Mechanistic understanding of ribosome activity will aid in the design of new antibiotics that combat the growing 'superbug' problem in today's hospitals. Over the past decade, we have focused on the mechanism by which the ribosome decodes genetic information ('the decoding problem', or 'tRNA selection'). By performing large-scale molecular dynamics simulations of the ribosome, we are able to examine the inner workings of this molecular machine. A key rearrangement of the parts of this machine is called 'accommodation'. Here, transfer RNAs (tRNAs) carrying protein building blocks (amino acids) move into the ribosome. We identified a new functional region of the ribosome ('the accommodation corridor') and predicted that certain parts of this corridor are important for ribosome function. Our predictions were recently validated in studies by three experimental groups. In an additional separate set of studies that combined our simulations with single molecule experiments, a new picture of ribosome function has emerged. Rather than the ribosome machine parts moving in lock-step, both simulations and single molecule experiments show the tRNAs making large-scale reversible excursions in a trial-and-error fashion. This picture is consistent with a dynamic energy landscape view of the ribosome. The recent advent of the direct electron detector camera for use in cryo electron microscopy single particle reconstructions of ribosome structures has produced an avalanche of high resolution structures of ribosomes rivaling X-ray crystallography. We are using the methods developed in our molecular simulations of the ribosome to produce automated high resolution fits of this new and exciting data.