A multiscale approach to sampling nascent peptide chains in the ribosomal exit tunnel.

Vincent A. Voelz, Paula Petrone and Vijay S. Pande. Pacific Symposium on Biocomputing, 14:340-352 (2009)

We present a new multiscale method that combines all-atom molecular dy-
namics with coarse-grained sampling, towards the aim of bridging two levels of
physiology: the atomic scale of protein side chains and small molecules, and the
huge scale of macromolecular complexes like the ribosome. Our approach uses
all-atom simulations of peptide (or other ligand) fragments to calculate local
3D spatial potentials of mean force (PMF). The individual fragment PMFs are
then used as a potential for a coarse-grained chain representation of the entire
molecule. Conformational space and sequence space are sampled efficiently us-
ing generalized ensemble Monte Carlo. Here, we apply this method to the study
of nascent polypeptides inside the cavity of the ribosome exit tunnel. We show
how the method can be used to explore the accessible conformational and se-
quence space of nascent polypeptide chains near the ribosome peptidyl transfer
center (PTC), with the eventual aim of understanding the basis of specificity
for co-translational regulation. The method has many potential applications
to predicting binding specificity and design, and is sufficiently general to allow even greater separation of scales in future work.