Mapping the Protein Fold Universe Using the CamTube Force Field in Molecular Dynamics Simulations

It has been recently shown that the coarse-graining of the structures of polypeptide chains as self-avoiding tubes can provide an effective representation of the conformational space of proteins. In order to fully exploit the opportunities offered by such a ‘tube model’ approach, we present here a strategy to combine it with molecular dynamics simulations. This strategy is based on the incorporation of the ‘CamTube’ force field into the Gromacs molecular dynamics package. By considering the case of a 60-residue polyvaline chain, we show that CamTube molecular dynamics simulations can comprehensively explore the conformational space of proteins. We obtain this result by a 20 μs metadynamics simulation of the polyvaline chain that recapitulates the currently known protein fold universe. We further show that, if residue-specific interaction potentials are added to the CamTube force field, it is possible to fold a protein into a topology close to that of its native state. These results illustrate how the CamTube force field can be used to explore efficiently the universe of protein folds with good accuracy and very limited computational cost.Author Summary: Modelling protein behaviour using computer simulations has progressively emerged in the last 50 years as a powerful strategy in structural and molecular biology. Over this period there has been a continuing interest in pushing the boundaries of this approach in terms of the size of the systems and the timescale of the processes that can be studied. Coarse-grained models offer in principle great opportunities in this context, but it has been extremely challenging to obtain force fields of accuracy comparable to that typical of fully atomistic models. We show here that the representation of protein molecules as self-avoiding tubes within the CamTube model enables the comprehensive, accurate and very fast exploration of the conformational space of proteins in molecular dynamics simulations. We illustrate in particular how the comprehensive mapping of the protein fold universe obtained using the CamTube model offers the possibility of analysing the behaviour of proteins in a wide range of non-native states.