MOLSImage: Combining Simulations and Imaging to Deliver Next Generation Tools for Studying Bacterial Cell Envelopes.

Bacteria are much smaller and simpler organisms than us; they only have one cell. Yet we still do not understand how they function. In particular it is frustrating that we do not understand how they are able to protect themselves from antibiotics - and indeed this is one of the main impediments to the rational development of effective novel antibiotics. Gram-negative bacteria are surrounded by a cell envelope which protects the cell and acts as a filter for the movement of molecules into and out of the cell; waste molecules are allowed to exit, essential nutrients are allowed to enter, whereas harmful molecules are by and large kept out. Currently we do not understand how this is achieved at the level of individual molecules let alone atoms.

The MOLSimage programme aims to develop a detailed understanding of the cell envelope that protects bacteria- this is of interest from a fundamental biophysics perspective, but also for the future will be important for developing new antibiotics. We will employ computational methods in combination with new advances in imaging technology being pioneered in the UK, to study the cell envelope in as much detail as possible. Rather than use the current approach of studying individual proteins or small groups of proteins, we will study realistically crowded systems to capture all of the relevant details. The combination of computational and experimental will be such that as increasing computing power becomes available, increasingly larger portions of the cell envelope will become tractable. Our methods will take the snapshots in time produced by the imaging methods, interpret and augment them such that additional molecules (that are too small to be picked up the imaging) are added and then the snapshot is subjected to molecular dynamics for time evolution of the systems.

The protocols and methods we develop will firmly place the UK in a world-leading position in terms of studying bacterial cell envelopes.