Ion channels are a ubiquitous family of pore-forming membrane proteins that play a critical role in a wide variety of signalling-based biological functions. Key to their function is the ability to change shape, from closed to open to inactivated states, to allow or prevent electrical current flows across cell membranes. These shape changes can be induced be a variety of stimuli, including voltage. One such family of channels that is of increasing interest to both Biggin and AWE are the voltage-gated sodium channels. As part of AWE’s ongoing work looking at predicting allosteric modulation of biological molecules, voltage-gated sodium channels, and in particular, Nav 1.7, have become an area of increasing interest to AWE. This has coincided with recent project work from the Biggin laboratory, examining the role of auxiliary beta subunits and their interaction with Nav 1.5.
Nav 1.7 is of interest in the context of pain and the design of new modulators is considered a potential route for the treatment of chronic pain. Recently, a cryo-EM structure with both auxiliary subunits and animal toxins bound was solved. Coupled with the above background, this presents an ideal confluence of events for us to address the following questions.
1. How well can we compute the free energy of binding of toxins and allosteric modulators of the Nav 1.7 channel?
2. What is the behaviour and role of the beta subunits on Nav1.7 and how does that differ from Nav 1.5?
3. Many compounds sit in the bilayer – how does the position within the bilayer influence binding affinity?
4. Can we develop computational methods that predict the how allosteric modulators (like toxins and auxiliary subunits) actually work in terms of altered dynamics?
Thus the project has two threads – aims 1, 2 and 3 are more applied, whilst aim 4 is more methodological. Of direct interest to AWE is the application of advanced molecular dynamics simulation techniques as applied to membrane-bound systems as routinely used by the Biggin laboratory. There is much scope for the use of advanced techniques (weighted ensembles, steered MD, etc) in the first two aims. The third aim, the development of new methodologies, which may include types of AI, is something that AWE have expertise in and can bring to the project. From both partners’ perspective, the overall goal of the studentship is to develop a method that has some broad application, but for which we will initially test out on Nav channels as there is (i) a large amount of existing experimental (and computational) data and (ii) likely to be even more structural information appearing in the near future.
Attributes of suitable applicants: We are looking for applicants from a chemical/biochemical background. Some simulation experience would be extremely valuable but is not necessarily a prerequisite as the techniques will be taught and learned in the laboratory. Similarly, experience of coding (python) would also be useful, but again is not a requirement.
Important Note: The on-site placement at AWE will require going through a security clearance process, and at a minimum that will require British citizenship.
This project is supported through the Oxford Interdisciplinary Bioscience Doctoral Training Partnership (DTP) studentship programme. The student recruited to this project will join a cohort of students enrolled in the DTP’s interdisciplinary training programme, and will be able to take full advantage of the training and networking opportunities available through the DTP. For further details please visit http://www.biodtp.ox.ac.uk