High-throughput, Multiscale modelling approaches for understanding bacterial signalling

Bacterial chemoreceptor proteins respond to local nutrients and toxins through binding events in receptor domains in the periplasm, causing a conformational change which is propagated into the cell where it triggers a signalling event through downstream effectors and ultimately changes in bacterial motion. Though the biophysical mechanism of signalling through the membrane has been studied extensively through a range of approaches, including mutagenesis of the transmembrane region, the precise mechanism is still unclear. Here I describe a novel high throughput approach to molecular dynamics simulation of transmembrane helices in a bilayer, where the process of building, running and analysing simulations across a cluster is entirely automated. Using this approach, I have been able to identify the role for small (0.15 nm) swinging-piston motions in carrying signals across the membrane. Alongside this, I describe simulations of complete 22 nm chemoreceptor models in a range of realistic environments, from model bilayers to 70 nm vesicles. Taken together, these approaches allow me to propose a mechanism of signal transduction across the membrane.