Abstract

Transmembrane helices play a multiple vital roles in cell function, including intercell signalling processes, channel gating and active transport. As such, there exists a considerable amount of data on the biological function and structural properties of naturally occurring helices and their mutants. Simulation studies can provide insight into the dynamics and behaviour of biomolecular systems in a variety of environments, but however such analyses are computationally expensive and typically difficult to automate. Coarse grain simulations are becoming an increasingly popular tool for understanding the properties of biological systems, overcoming canonical limits of atomistic simulations such as timescale or system size. Both such techniques involve several manual steps, including system build, simulation set up and analysis. Here we present Sidekick, a piece of software which automates these processes to allow for the set up of massive numbers of coarse grain simulations on the basis of a small set of input sequences, or a single sequence and a scanning mutation. We validate the methodology by comparison with data from high throughput experiments relating the insertion of peptides into the membrane by the translocon. We then use the technique to predict the biophysical changes induced by a variety of mutations of bacterial methyl accepting chemoreceptor protein transmembrane helices described in the literature. By observing the change in positions and orientations of the helix with different mutations, we propose that a swinging piston model dominates the signalling event, though there may be a lesser role for rotation of the helix.

His website: http://sbcb.bioch.ox.ac.uk/hall.php