Synthetic beta cells for fusion-mediated dynamic insulin secretion

Generating artificial pancreatic beta cells by using synthetic materials to mimic glucose-responsive insulin secretion in a robust manner holds promise for improving clinical outcomes in people with diabetes. Here, we describe the construction of artificial beta cells (AβCs) with a multicompartmental 'vesicles-in-vesicle' superstructure equipped with a glucose-metabolism system and membrane-fusion machinery. Through a sequential cascade of glucose uptake, enzymatic oxidation and proton efflux, the AβCs can effectively distinguish between high and normal glucose levels. Under hyperglycemic conditions, high glucose uptake and oxidation generate a low pH (<5.6), which then induces steric deshielding of peptides tethered to the insulin-loaded inner small liposomal vesicles. The peptides on the small vesicles then form coiled coils with the complementary peptides anchored on the inner surfaces of large vesicles, thus bringing the membranes of the inner and outer vesicles together and triggering their fusion and insulin 'exocytosis'

Harvesting free energy landscapes in biological systems

A sophisticated mechanistic investigation of biological processes is the starting point for the calculation of accurate free energy figures, which enable comparison with experimental results. Applied to drug discovery, the use of molecular methods can guide the formulation and optimisation of novel drugs, specifically targeting molecular processes as they are learned from simulations. This is illustrated here based on two examples, the study of secondary DNA structures (G4s) as target for small gold-based molecules, and the investigation of the mechanisms of glycerol permeation via the membrane channel aquaglyceroporin-3 (AQP3). Both approaches leverage the enhanced sampling efficiency of accelerated molecular dynamics