Sculpting Dynamic Amphiphilic Structures

Biomembranes lie at the heart of most biological function, and lipid membranes are increasingly finding a wide range of novel applications in biotechnology and nanomedicine. Such self-assembled amphiphilic interfaces can adopt an astonishing range of complex shapes and liquid-crystalline structures ordered in 1, 2 or 3 dimensions, over length scales stretching from 2 - 3 nanometres, to microns. Gaining an understanding at a molecular level of how interface structure, ordering, dynamics and micromechanics depend upon chemical structure and composition, and thermodynamic variables such as temperature, hydration, and pressure, is the key to learning how we can manipulate such self-assembled soft interfaces to create novel and useful structures and new technologies, and this is the main aim of this Programme. We have identified three key underpinning basic science challenges: 1) asymmetry; 2) patterning; 3) curvature, long-range organisation and symmetry. There are four main aspects underlying these challenges which we consider are of crucial importance: i) compositional asymmetry and dynamics of amphiphile flip-flop across bilayers; ii) lateral segregation, line tension and microdomain formation; iii) membrane curvature and curvature elasticity; iv) charge and dipolar interactions between lipid headgroups. Furthermore, there is a complicated coupling between all of these four aspects, and this is where we will focus much of our attention. We have assembled a team of five leading UK University research groups, spanning Chemistry, Physics and Biophysics. The groups have complementary expertise covering laboratory-based and synchrotron time-resolved X-ray diffraction, neutron scattering, solid-state nuclear magnetic resonance, calorimetry, biomolecular force microscopy, Langmuir trough and microfluidics technologies, linear and non-linear spectroscopies, atomic force microscopy, spectroscopic and optical imaging, optical tweezers, microrheology, and theory. These approaches will be used to attack different inter-related aspects of the three key basic science challenges. We will ensure an efficient translation and synthesis of all of the findings, by a tightly- regulated management structure, and by regular meetings and staff exchanges between the five research groups. Building on the engineering rules and technologies developed previously in the programme, we will integrate the earlier work to develop lipid structures into active lipid systems such as: self-encapsulated droplet interface bilayer networks in water; patterned asymmetric vesicles of defined size: coupling microfluidics with smart droplet microtools; phospholipid phases and vesicles in thermal gradients. We will then use this knowledge to develop three demonstration systems: i) Artificial Organelles. The development of artificial organelle machines which mimic some of the remarkable functions and properties of biology will lead to new approaches for personalized healthcare. ii) Rapid drug-membrane binding screen. A compartmentalised, rapid drug screening device will allow parallel measurements of drug interactions with a number of artificial plasma membrane mimics (PMMs) formed by an array of parallel droplet interface bilayer or vesicle networks. iii) In-Cubo Crystallization of Large Membrane Proteins. Learning how to swell lipid cubic phases will unlock our ability to construct cubic scaffolds with unit cell dimensions of the order of tens or hundreds of nanometres, allowing incorporation of large membrane proteins (>50kD), which are major drug targets for the pharmaceutical industry. Further biological and biotechnological applications will be developed during the course of the Programme by the current Investigators and a wider group of industrial and academic collaborators, who will be brought into the Programme as appropriate.